"Never doubt that a small group of thoughtful, committed citizens can change the world. Indeed, it is the only thing that ever has."

Margaret Mead

Review article
peer-reviewed

An Update to Hallmarks of Cancer



Abstract

In the last decade, there has been remarkable progress in research toward understanding and refining the hallmarks of cancer. In this review, we propose a new hallmark - “pro-survival autophagy.” The importance of pro-survival autophagy is well established in tumorigenesis, as it is related to multiple steps in cancer progression and vital for some cancers. Autophagy is a potential anti-cancer therapeutic target. For this reason, autophagy is a good candidate as a new hallmark of cancer. We describe two enabling characteristics that play a major role in enabling cells to acquire the hallmarks of cancer - “tumor-promoting microenvironment and macroenvironment” and “cancer epigenetics, genome instability and mutation.” We also discuss the recent updates, therapeutic and prognostic implications of the eight hallmarks of cancer described by Hanahan et al. in 2011. Understanding these hallmarks and enabling characteristics is key not only to developing new ways to treat cancer efficiently but also to exploring options to overcome cancer resistance to treatment.

Introduction & Background

The transformation of a normal cell into a neoplasm is a complex process. Hanahan et al. summarized hallmarks of cancer including six core hallmarks, two emerging hallmarks and two enabling characteristics [1]. The bidirectional communication between a cancer cell and tumor microenvironment (TME) and macroenvironment creates a tumor-supportive environment and premetastatic niche, which helps cancer cell to develop, grow and metastasize [2]. In the last decade, there has been tremendous progress in research to understand the hallmarks of cancer. Hanahan et al. emphasized the importance of autophagy, independently or in association with apoptosis, as a barrier that needs to be avoided by cancer cells to reach efficient tumorigenesis, as part of resisting cell death hallmark of cancer [1]. Although they call attention to the cytoprotective effect of autophagy on cancer cells in the face of nutrient starvation and toxic effects of radiotherapy and chemotherapy, possibly leading them to a state of dormancy [1], little was known at that time about the role of autophagy on tumor progression and if this could be seen as another hallmark of cancer. Since then, evidence had emerged on the pro-survival role of autophagy in cancer cells. In this review, we first proposed a new hallmark - pro-survival autophagy. Then, we modified two enabling characteristics that play a major role in enabling cells to acquire the hallmarks of cancer and discussed the recent updates, therapeutic and prognostic implications of the eight hallmarks of cancer described by Hanahan et al. in 2011 (Figure 1) [1].

Review

New hallmark of cancer

Pro-survival Autophagy

Autophagy is an important process in cell death, conservation of protein homeostasis and maintenance of normal organelle function, as it removes damaged structures under cell environment stress conditions. Autophagy can occur in three different pathways: chaperone-mediated autophagy (with the participation of intermediate ligand chaperone proteins like HSP70s), microautophagy (direct engulfment of small cytoplasmic structures by lysosomes), and macroautophagy (where cytoplasmic components are sequestered into the autophagosome and degraded on lysosomes) [3].

Autophagy is essential for oncogenic K-Ras-induced malignant cell transformation in human breast epithelial cells, as the mRNA protein levels of ATG5 and ATG7 (autophagy-specific genes) were increased in cells overexpressing K-Ras and that targeted suppression of these genes inhibited cell growth and tumor formation [4]. Tan and colleagues observed that autophagy was increased in hypoxic regions of tumors in three different human tumor cell lines and hypoxia-induced cell death was more rapid in their autophagy-deficient variants with shRNA knockdown of the genes ATG7 and BECLIN1 [5]. Amid situations of metabolic stress in tumors, autophagy is required to maintain the pool of functioning mitochondria through recycling damaged or nonfunctional intracellular material. This process ensures the supply of nutrients (like amino acids and fatty acids) and ATP, needed for tumor growth [6]. Deficiency in autophagy leads to the accumulation of abnormal mitochondria, lack of ATP, and key tricarboxylic acid (TCA)-cycle intermediates, resulting in mitochondrial dysfunction. Mitochondrial dysfunction leads to the generation of toxic reactive oxygen species (ROS) and mitochondrial damage [7] and is an important process in pancreatic tumor growth [8], as well as liver tumor formation in ATG5 and ATG7 deficient mice [9].

Although not totally clear, some studies suggest a positive correlation between autophagy and epithelial-mesenchymal transition (EMT), which is needed in cancer progression and metastasis, probably via p62 (an autophagy adaptor protein) and tumor growth factor β (TGF-β), which is the most important regulator of EMT in human cancers [10]. Knockdown of BECLIN1, an important autophagy activator, was shown to suppress EMT in colon cancer [11], and its activation via phosphorylation by ULK2 promotes EMT in lung cancer cells [12].

Because autophagy facilitates cancer cells' survival in an environment with hypoxia and metabolic stress, it reduces tumor necrosis and consequently the infiltration of macrophages in the primary tumor, that is a required step for metastasis [10]. Also, autophagy provides tumor cells the ability to avoid anoikis, a process of detachment-induced programmed cell death, resulting from loss of, or inappropriate cell adhesion from the extracellular matrix (ECM) via RNA-like endoplasmic reticulum kinase (PERK), that promotes autophagy and ROS detoxication in mammary epithelial cells [13], upregulation of BNIP3 mediated by ERK/HIF-1α pathway induced autophagy by suppressing mTOR/S6K1 [14] and deficiency of miRNA-30a, a tumor suppressor that targets Beclin-1 and ATG5 in hepatocellular carcinoma [15]. Anoikis resistance also occurs via the regulation of SDCBP/MDA-9/Syntenin in gliomas [16].

Cancer stem cells (CSCs) that play an important role in tumor recurrence and resistance to anti-neoplastic treatment strategies, seem to have a role in tumor maintenance and function related to autophagy. Some autophagy markers like ATG5, ATG12, and LC3B were found to be overexpressed in dormant stem cell-like breast cancer cells [17] and BECLIN1 staining areas were found to be surrounded by actively proliferating cells [18]. In pancreatic cancer, HIF-1α and autophagy regulate the balance between CSCs and non-CSCs [19]. A subset of CSCs showed resistance to chemotherapy and was associated with a high autophagy activity [20].

Autophagy, as an important survival mechanism against various cellular stresses, can induce resistance to various anti-cancer therapeutic agents (cytotoxic chemotherapy, radiotherapy, molecular target agents and antiangiogenic agents) by reducing ROS damage, blocking apoptosis, and maintaining the CSC pool [10]. Some therapeutic agents like imatinib and paclitaxel have already known mechanisms of resistance related to autophagy [21,22].

The better comprehension of pro-survival autophagy leads to studies assessing classes of therapeutic anti-cancer targets in this field, most of them with preclinical evidence, but some are still ongoing clinical trials. One of them are class III isoform of phosphoinositide 3 kinase (PI3K), that induces autophagy by generating PI3-phosphate, needed for the formation of autophagosome membrane [23]. Wortmannin, a covalent irreversible binding inhibitor of PI3K have demonstrated enhanced response when associated to cisplatin in urothelial cancer [24], and spautin-1, which blocks autophagy by deubiquitinating Beclin-1, improved imatinib-induced apoptosis in chronic myeloid leukemia [25]. The ULK1 inhibitor SBI-0206965 attenuated cell survival in non-small cell lung cancer tumor cells [26], reduced tumor growth and metastasis in neuroblastoma cells [27] and exhibits a potential anticancer effect against clear cell renal carcinoma [28]. ATG4 inhibitors NSC185058 and Ticonazole, respectively, exhibit anti-tumor effect in osteosarcoma tumor models in vivo [29] and enhance the cytotoxicity of chemotherapeutic drugs, suppressing tumor viability [30]. Hydroxychloroquine (HCQ) attenuates lysosomal acidification, resulting in obstruction of the activity of the lysosomal degradative enzyme and inhibiting autophagy, but at a high concentration with greater cytotoxicity [31]. Lys05, a potent autophagy inhibitor derivative of HCQ demonstrated anti-tumor activity [32]. Bafilomycin-A1 specifically obstructs V-ATPases and blocks autophagy flux by inhibiting lysosomal acidification, facilitating cell cycle arrest and caspase-dependent apoptotic cell death in colon cancer [33].

The importance of pro-survival autophagy is well established in tumorigenesis, as it is related with a lot of events in cancer progression and critical for some of them in various types of cancers. Besides that, autophagy is a potential anti-cancer therapeutic target. For this reason, autophagy is a good candidate for a new hallmark of cancer.

Enabling characteristics

Tumor Promoting Microenvironment and Macroenvironment

Hanahan et al included tumor-promoting inflammation as one of the enabling characteristics of cancer [1]. Most tumors trigger a tumor-promoting inflammatory response [34] which is recognized as the seventh hallmark of cancer [35]. Inflammation plays a major role in every step of cancer development [34,36].

Tumor initiation: The inflammatory microenvironment increases mutations and genetic instability either by producing ROS and reactive nitrogen intermediates or via cytokines that stimulate ROS [34,36]. Inflammatory cytokines express activation-induced cytidine deaminase and inhibit p53 thereby increasing genetic instability and mutations [34]. Inflammation promotes stem cell expansion [34].

Tumor promotion: Inflammatory response induces genes promoting cell proliferation and survival [34]. Tumor associated macrophages in response to hypoxia produce vascular endothelial growth factor (VEGF) promoting neo-angiogenesis [34,36].

Tumor metastasis and invasion: Inflammatory myeloid cells and cancer cells produce tumor growth factor β that helps in EMT and metastasis [34]. Inflammatory cells produce proteases to facilitate proteolysis, that is required for invasion [34,36]. Survival of metastatic seeds is assisted by cytokines [34]. Inflammation also upregulates adhesion molecules that facilitate the attachment of metastatic cells in target organs [34].

The role of several inflammatory cytokines as prognostic markers is being studied. Higher levels of IL1 β, IL1Ra, IL18, and IL1α in breast cancer tissues and significantly higher IL1 β levels in stage II, III or IV breast cancers were reported [37]. Higher levels of IL-17+ and IL-22+ T lymphocytes are associated with the progression of basal-cell and squamous cell skin cancers [38]. Targeting these inflammatory cytokines might have a potential therapeutic effect in these cancers.

The inflammatory cells acquire pro Vs antitumor capabilities depending on the interaction with TME and the macroenvironment. In addition to tumor-promoting inflammation, there are several studies in the last decade highlighting the bidirectional interaction between a cancer cell and microenvironment as well as macroenvironment that is key for a cancer cell to develop, survive, progress, and invade. Tumor exosomes play a major role in communication with TME and the macroenvironment to promote tumor growth and metastasis. Tumor exosomes modify stroma and immune cells creating a metastatic niche supporting the seeding of tumor cells [39].

Tumor macroenvironment also referred to as tumor organismal environment includes metabolic, endocrine, lymphatic, hematopoietic, immunologic, microbiotic and neurogenic environments [40]. Metabolic imbalance in the macroenvironment seen in two major metabolic disorders, diabetes and obesity, is shown to be associated with promoting tumor development [40]. Hormonal changes in the endocrine macroenvironment impact tumor growth and tumor-promoting inflammation [2]. Tumors also control the endocrine environment via paraneoplastic syndromes [41]. The lymphatic environment helps tumors communicate with systemic circulation [40]. Hematopoietic and immunologic environments influence bone marrow thereby facilitating tumors to suppress antitumor immunity [40]. Recent studies demonstrated the role of gut microbiota in inflammation-promoting tumorigenesis. Gut microbiota promotes tumor progression via the production of certain inflammatory cytokines such as TNFα, IL-6, and IL-17 [2]. Gut microbiota dysbiosis was reportedly related not only to local inflammation-promoting tumor development but also distant cancer such as hepatocellular carcinoma and breast carcinoma and liver metastases in lymphoma [40]. Further studies are required to investigate the effect of modifying gut microbiota dysbiosis in promoting antitumor immunity. The neurogenic environment is particularly gaining interest recently. Zhao et al demonstrated that denervation suppresses gastric tumorigenesis [42]. Furthermore, the concept that adrenergic nerves drive tumor angiogenesis was recently described [43]. Tumor exosomes are reported to control tumor-promoting neurogenesis and glutamate released from local neurites is reported to facilitate breast to brain metastases [40]. Sympathetic and parasympathetic signaling showed a role in the growth of prostate cancer [40].

Cancer Epigenetics, Genome Instability and Mutation

Epigenetics is defined as heritable modifications in gene expression induced via changes in chromatin structure barring adjustments of DNA sequence [44,45]. Accumulating evidence indicates that, without genetic alterations, epigenetic mechanisms are implicated in the acquisition of malignant phenotype [46]. These genetic and epigenetic alterations interact at all levels of the development of most cancers, working collectively to promote cancer progression [47]. The genetic foundation of cancer is widely accepted; however, recent research proposes that epigenetic changes may also be the key initiating events in some types of cancer [48].

Epigenetic mechanisms that regulate chromatin structure can be divided into four essential categories - DNA methylation, covalent histone modifications, non-covalent mechanisms such as the incorporation of histone variants and nucleosome remodeling and non-coding RNAs together with microRNAs (miRNAs) [49,50].

The altered epigenetics of most cancers cells suggests that epigenetic therapies should have a fundamental clinical impact [47]. The main question remains if we can use our understanding of the epigenetic regulators to find so-called synthetic vulnerabilities that would give us new therapeutic possibilities in the treatment of cancer?

In 2011, Hanahan and Weinberg added genome instability into their list of fundamental characteristics of cancer, particularly as an enabling characteristic [1]. The result of the failure of crucial teams of proteins that protect the DNA of the genome from being mutationally corrupted, rearranged, and re-programmed is ‘oncogenic’ mutations that convey on cancer cells various hallmark capabilities. Very recently, Pan-cancer Analysis of Whole Genomes (PCAWG), an international collaboration to identify common patterns of mutation, published an analysis of 2,658 whole cancer genomes across 38 tumor types (https://www.nature.com/collections/afdejfafdb/Feb2020). One of the major studies of this project shows that each tumor had four or five driver mutation on average and at least one driver mutation was found in about 95% of the tumor samples compared with just 67% with exome sequencing [51]. Cancer develops through a process of somatic evolution [52]. Early oncogenesis is characterized by mutations in a constrained set of driver genes and specific copy number gains [52]. However, the mutational spectrum changes significantly throughout tumor evolution in 40% of samples. New patterns of mutations were reported that result from environmental exposures such as tobacco smoke [53]. Endogenous sources of mutation and epigenomic features promote genomic instability during cancer evolution [54]. Recent work has shown that even in repair-sufficient cells, endogenous and oncogenic stress can occasionally overwhelm the normal genome maintenance pathway [54].

Solid tumors of epithelial origin with extreme levels of genomic instability are associated with a potentially better prognosis compared with intermediate level [55]. Also, cancers with extreme levels of genomic instability may be teetering on the brink of a threshold where so much of their genome is adversely altered that cells rarely replicate successfully [5] these cancers are more immunogenic than other cancers with a less extensive burden of genetic aberrations. Pua et al. reviewed studies that established a link between inflammation and the pathophysiology of cancer, and this stems largely from the genomic instability that results from inflammatory cytokines and signaling [56]. Inflammation leads to suppression of cell cycle arrest and apoptosis, further allowing the proliferation of mutant cells.

Recent fast progress in CRISP/Cas9 base editing technology has made it technically highly feasible to generate site specific nucleotide substitutions of DNA by manipulating highly intricate DNA repair pathway [57].

An update to 2011 hallmarks of cancer

Sustaining Proliferative Signaling

One primary hallmark described by Hanahan et al is the cell's ability to become auto-sufficient and enable signals to sustain a continuous proliferative pathway [1]. Some messages can be extracellular growth signals, which bind to transmembrane receptors or transcellular and intracellular stimuli [1]. The mitogenic signals and regulation are complex, and the activity seems to be controlled from one cell to the others as paracrine signaling [1]. In cancer cells, this process is better comprehended, and mutant cells obtain the ability to replicate in many ways [58-61].

The mitogenic stimulus can be generated by an upstream receptor pathway or by downstream and intracellular circuits.

Upstream circuits: Tumor cells may induce the surrounding cells to support their growth with various growth factors [62,63]. The cancer cell may have the ability to increment the number of displayed transmembrane receptors. It will make them hyper-responsive to GF ligands and increase the proliferative rate. These receptors usually have intracellular tyrosine kinase actions. For example, EGF-R/erbB in Breast, stomach, and brain tumors. A structural modification can make these ligand-independent receptors easily firing. For example, some truncated versions of the EFG missing part of their cytoplasmic domain fire continuously [61].

Downstream cytoplasmic pathways may be GF independent and result in continuous activation of proliferation.

a. Somatic mutations trigger more downstream circuits: As shown by Davies and Samuels, 40% of melanomas have some mutations in B-Raf protein result in continuous signaling generated by the activation of Raf to MAP- kinase (mitogen-activated protein). Mutations in phosphoinositide 3-Kinase (PI3-kinase) isoforms may hyper-stimulate the signaling pathway [64,65].

b. Disturbances of Negative-Feedback mechanisms that attenuate proliferative signaling: Antiproliferative signals control and maintain cell homeostasis by inhibition of proliferation [66-69]. Failure in a negative feedback mechanism will allow the cell to replicate indefinitely. For example, the Ras oncoprotein: does not increase the activity of the signal. Instead, it compromises an enzyme action, the Ras GTPase, which is responsible for transitory signal in the Ras pathway. The mutation compromises the negative feedback and results in continuous activation and signal transduction. The PTEN phosphatase counter-acts PI3K Kinase. If PTEN presents a loss-of-function mutation, it may result in the amplification of PI3K signaling, leading to tumorigenesis. mTOR kinase results in negative feedback and inhibition of PI3K signal. The repression of mTOR will result in increased PI3K activity and its effector Akt/PKB, causing dampening in the antimitotic effects of mTOR inhibition [70,71].

These mechanisms of turning off the negative control of cell proliferation probably contribute to drug resistance. The excessive proliferative stimulus may result in cell senescence or apoptosis [72-74]. This contradictory behavior may reflect intrinsic cellular protection, which attempts to eliminate cells presenting inappropriate proliferation signals. Some cancer cells probably adjust their tolerance to abnormal oncogenic protein levels by deactivating their apoptosis or senescence-inducing pathways.

Evading Growth Suppressors

Cancer cell needs to avoid antigrowth signals to thrive [75]. Growth suppression resides centrally in pRb and p53, which operate as part of a large network that is inter-ligated in a way that favors redundancy and more efficient control. Tumor cells escape these antiproliferative control by loss of function of these genes or alterations in response to their close regulators as TGFβ or immediate downstream targets of its action, as CDK4 and its inhibitory proteins [75] and contact inhibition of cell growth, like NF2 / Merlin and LKB1 epithelial polarity protein, that when disrupted can also facilitate uncontrolled proliferation as seen in cancer tissues [1].

Several other mechanisms, directly or not linked to pRb and p53 pathways, positively or negatively related to antiproliferative control, emerged in the last years and confirm the evasion of growth suppressors as an actual hallmark of cancer, helping to understand widely the complexity of this system, which can be a potential therapeutic target in many types of cancers.

Alternative Reading Frame (ARF)

ARF is a tumor suppressor protein encoded in the INK4b/ARF/INK4a gene locus located on chromosome 9p21 in humans that activate p53 in response to oncogenic signals, such as c- MYC [76]. Although transcriptional regulation of ARF has been known since the late 1990s, most of its post-translational regulation have emerged after 2004, that this protein could be ubiquitinated and degraded via proteasomal degradation [77] and the enzymes involved in this process like ULF, SIVA1 and MKRN1 were discovered only after 2010 [78-80]. Besides that, ARF can also suffer lysosomal degradation mediated by CHIP and HSP90 [81]. Inhibition of HSP90 by geldanamycin can induce cell growth retardation and cellular senescence in human normal cells and mouse embryonic fibroblasts [81]. De-ubiquitination of ARF by USP10, which results in stabilization of ARF and promotes cellular senescence [82].

The low expression of ARF mRNA is frequently observed in human cancers and is usually caused by hyper-methylation on the CpG island of the ARF promoter or deletion of the genetic region and has been described in breast, bladder, colon, liver, gastric, lung, oral, prostate and brain cancers and has emerged as a predictor of poor prognosis in breast, head and neck, colon and bladder carcinomas [82].

Galectins

Glycosylation changes had emerged as an important process in cancer progression and among the glucan-binding proteins that deciphers the information encrypted by the glycoma, galectins had great importance [83]. Gal7 showed to be a proapoptotic Galectin induced by TP53 in colorectal and urothelial cancer [84,85]. Gal7 expression can be silenced by methylation of CpG islands in the LGALS7 gene and hypermethylation at a region of the exon2 that is predicted to be a TP53-binding [86]. Nevertheless, the overexpression of Gal7 had a tumor-promoting behavior in thymic lymphoma and breast cancer [87,88], a paradoxical effect that could be explained by the observation that both NF-κB-binding and TP53 transcription factors can control its expression. In breast cancer cell lines, WT and mutant TP53 increased NF-κB activity and up-regulated Gal7 expression. Conversely, in a p53-null cell line, with high NF-κB activity, Gal7 undetectable, suggesting NF-κB-TP53 complex to be required to the LGALS7 promoter activation [89]. Reciprocal regulation between Gal7 and TP53 was also proposed when observed that Gal7 was able to impede TP53 translocation to the nucleus [90]. Another galectin, Gal3, was shown to be repressed by TP53, with increased expression of Gal3 been observed in p-53 mutant tumors [91]. In human prostate cancer cells, knockdown of Gal3 promoted a cell cycle arrest at the G1 phase, up-regulation of nuclear p21, and hypophosphorylation of Rb [92].

Melatonin

Melatonin was found to induce phosphorylation of p53 at Ser-15 causing proliferation inhibition and prevention of DNA damage accumulation [93]. The treatment with melatonin resulted in increased p53 expression in breast cancer and prostate cancer cells and expression of BRCA 1 and BRCA 2 in breast cancer cells [94,95].

Micro-RNAs (miRNAs)

Many critical cell proliferation pathways involve miRNAs, dysregulation of which is responsible for evading growth suppressors and sustaining proliferative signaling in cancer cells. Some of these miRNAs interfere on E2F proteins expression, that are cell cycle regulators of cell proliferation, as miR-17-92 that inhibits E2F1 translation through breaking the positive feedback between c-Myc and E2F1 [96] and was found to regulate E2F2 and E2F3 translation [97] in a feedback system that promotes normal cell proliferation. The overexpression of miR-17-92 in some tumors like B-cell lymphomas can disrupt this feedback loop and lead to unbalanced cell proliferation [98].

Other microRNAs negatively regulate CDK inhibitors, being needed to the cell cycle progression and cell proliferation, as miR-221/222, which has been identified to directly target p27Kip1 in glioblastoma cells [99] and that its overexpression can be found in a variety of human tumors [100], confirming the oncogenic role of this pathway. MicroRNAs can also directly regulate the expression of CDK and cyclins, as an example of miRNA-545, that promotes cell-cycle arrest in lung cancer cells by repressing the expression of cyclin D1 and CDK4 [101].

Long Noncoding RNAs (lncRNAs)

There are more than 10,000 lncRNAs in the human genome and they are implicated in almost all hallmarks of cancer, including acting as regulators of tumor suppressor genes and molecules that regulate the cell cycle [102]. The lncRNA HULC regulates the expression of P18 protein (an inhibitor of CDK4 and CDK6) and its high expression is correlated with hepatocellular carcinoma. H19 derives miR-675, which negatively regulates RB and p53 [103]. LINCRNA-P21 inhibits CDK2 and is found to be downregulated in hepatocellular carcinoma [104], the same way that PTENP1 downregulation promotes malignant behavior in head and neck squamous cell carcinoma [105]. HEIH negatively regulates the expression of CDK inhibitors P15, P16, P21 and P57, via EZH2 [106] and ANRIL positively regulates proliferation by recruitment of polycomb repression complex 2 to the INK4 locus and represses the transcription of P15 [107].

Resisting Cell Death

Cancer formation involves different changes in the genome [108] and a series of genetic alterations and failure of intracellular checkpoints [109]. Defective apoptosis is a hallmark of cancer [75] and understanding its mechanisms can help in designing efficient therapeutic strategies.

Apoptosis pathways are classified into two types: extrinsic (receptor-mediated) and intrinsic (mitochondria-mediated). These pathways may be linked, molecules involved in one can affect the other one, and they can also be involved in other cell processes [110]. The extrinsic pathway requires the successful interaction of specific receptors found on cell membranes and their respective ligands. The intrinsic pathway may be activated by different stimuli, like radiation, free radicals, viral infections, and serum/growth factor withdrawal [110]. The triggers in the mitochondria-mediated pathway change the inner mitochondrial membrane permeability resulting in the loss of the mitochondrial transmembrane potential, the release of pro-apoptotic proteins and the arrest of the bioenergetic function of the organelle [110]. This pathway does not include special receptors; thus, its exploitation may be a key to successful cancer therapy [110].

The regulation of apoptosis is also complex. The Bcl-2 family includes different proteins that influence apoptosis: some of them interact with mitochondrial proteins and prevent them from forming pores, inhibiting the release of apoptogenic factors, others neutralize the anti-apoptotic proteins [111,112]. Interaction between pro-and anti-apoptotic proteins is another way of affecting the survival and death of the cell. Modulation of the regulatory proteins is a major factor contributing to the survival advantages of cancer cells. The inhibitors of apoptosis (IAPs) block cell death by regulating the caspase cascade and may influence both the intrinsic and extrinsic pathways in the cells. The tumor suppressors, like p53, have several action mechanisms, one of which affects mitochondria by p53 physically interacting with Bcl-2 and antagonizing its anti-apoptotic function. ROS also influence cell death signaling. Though ROS can influence the extrinsic death pathway by making the environment conducive for effective interaction of receptors and ligands, the intrinsic pathway is more susceptible to ROS. There are multiple targets for ROS in mitochondria, linked to its primary function of a powerhouse in cells [113].

The main issue with conventional therapies in cancer treatment (surgery, radiation, and chemotherapy) is the evolution of adaptive mechanisms in cancer cells. Adaptive mechanisms may include upregulation of pro-survival proteins, suppression of pro-apoptotic proteins and defects in p53 signaling pathways. Many anticancer agents that target pathways involving deregulation of proteins like p53 lead to resistance, so direct targeting of mitochondria may be a promising strategy in attempts to restore the cells’ ability to die [114-117].

In conclusion, new drug targets can be identified and target selective therapeutic methods could be developed through analysis of apoptotic signaling pathways and apoptosis resistance mechanisms.

Enabling Replicative Immortality

The ability of tumoral cells to achieve replicative immortality, allowing subsequently macroscopic growth, has been widely accepted as a hallmark of cancer [1]. Several studies point out the central role of telomeres maintenance necessary to bypass the natural cell aging process [118,119]. The gradual telomere shortening, which occurs after multiple cell divisions, regulates the life span of the cells and their capacity for replication [120]. When a telomere becomes too short and reaches a critical length, usually after 50 to 60 cell cycles, the cell senescence is induced [119,121]. Subsequently, genes like p53, p21 and Rb/p16 INK4A that are associated with growth cell arrest and apoptosis, are activated. When a short telomere is not recognized by the cell cycle arrest checkpoint, it will undergo further shortening and DNA damage proteins will be activated, leading to homologous recombination or non-homologous end joining of the chromosome, generating thereby aberrant chromosomes. Such a cell with unstable DNA is defined in the crisis phase and normally undergoes apoptosis. This process of telomere shortening inducing senescence or crisis/apoptosis in normal cells is considered a sort of natural tumor-suppressing mechanism.

In carcinogenesis, cells can activate mechanisms of telomere maintenance to overcome the cell senescence or apoptosis caused by telomere shortening. Several mechanisms of telomere maintenance have been identified and include telomerase gene hTERT promoter mutations [122], telomerase reactivation, oncogenes and tumoral suppressor genes mutations, alternative lengthening of telomeres (ALT) - telomerase independent mechanism [123].

According to data, in 85%-90% of cancer cells, the mechanism of telomere stabilization is reached by telomerase activation and only 5%-15% exhibit an ALT pathway [124-126].

Despite the upregulation of telomere reverse transcriptase (TERT) expression via promoter mutation [127-132] and telomerase activation in most malignant cells, telomeres in cancer are shorter than those in normal tissues: as several studies show, 90% of cancer cells contain short telomeres and high levels of telomerase activity. In fact, it seems the shorter the telomere is, the higher the cancer aggressiveness, and the poorer the prognosis [132,133]. For example, 75% of oral carcinomas, 80% of lung cancers, 84% of prostate cancers, 85% of liver cancers, 93% of breast cancers, 94% of neuroblastomas, 95% of colorectal cancers, and 98% of bladder cancers have detectable telomerase activity [134,135]. Some cancer cell lines keep noticeably short telomeres (prostate PC-3, stomach MKN74 and breast HBC-4 cancer cells) and elongate their telomeres by TERT over-expression [136,137]. Patients with glioblastoma with isocitrate dehydrogenase 1 (IDH1) mutation and ALT activation, which is associated with longer telomeres, showed better clinical outcome than those with ALT negative tumor [133,134,138-140]. Interestingly, TERT or even telomerase activity is inversely correlated with telomere length [133,141].

Huang et al. showed that upon mitogen stimulation, not all but only a small subpopulation of T- cells reactivate telomerase and preferentially elongate short telomeres [142]. It is possible that there are various cell subpopulations with long to short telomeres during cancer development [142]. Furthermore, genomic instability elicited by shortened telomeres might be advantageous to cancer evolution [143]. In fact, induction of chromosomal instability via the telomeric DNA damage response followed by end-to-end fusions promotes oncogenic transformation [144,145]. Telomerase activation confers immortality but not neoplastic properties to cancer cells [135,146], given that malignant transformation requires a multi-step process [135,147].

Nevertheless, should the precise moment of telomeres shortening triggering telomerase activation be known, this could then have major effectiveness in stopping the tumor. This remains a challenge for future researchers [126].

Inducing Angiogenesis

Angiogenesis is a physiological process, that determines the formation of new vessels from preexisting ones. Angiogenesis is involved not only in embryonic development but also in damage and recovery. This process is tightly regulated and controlled by different mechanisms. By contrast, in pathological conditions (like cancer) angiogenesis is dysregulated and hyperactivated. The relationship between angiogenesis and cancer was first described in 1968 when several proangiogenic factors were discovered [148,149].

Tumor angiogenesis is a multistep process, and its main generator is hypoxia in tumor cells due to inadequate blood supply. It causes the production of angiogenetic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor α, TGF-β, tumor necrosis factor (TNF)-α etc. by cancer cells, which bind to endothelial cell receptors of the vessels and initiate above mentioned process. Whenever the endothelial cells are stimulated, the secretion of matrix metalloproteinases (MMPs) is prompted, which causes degradation of the basal membrane. This process allows endothelial cells to invade surrounding tissues and start forming new vessels. In addition, factors such as angiotensin-1, -2, and their receptor Tie-2c are needed for the stabilization of newly formed vessels [150,151].

Angiogenesis plays a key role in cancer and according to many studies level of angiogenetic factors is correlated with tumor aggressiveness and has a strong predictive role [1,152].

Activating Invasion and Metastasis

Metastasis is a hallmark of cancer and the cause of most cancer-related deaths [1]. It is a multistep process by which tumor cells leave the primary tumor, travel to a distant site, and establish secondary tumors in distant organs (Figure 2) [1,153].

There are a variety of determining factors that govern the flexibility of a primary tumor to metastasize to different organs. These include genetic disorders to growth factors within the environment of the first tumor, the flexibility of tumor cells to detach from neighboring cells, the flexibility of tumor cells to digest the ECM and invade the vasculature. The tumor cells reorganize their cytoskeleton, express adhesion molecules on their surface to acknowledge adhesion sites, and chemotaxis or become migratory and motile resulting in loss of contact inhibition, and ultimately migrate to inappropriate locations giving rise to metastatic dissemination.

In vivo as well as in vitro studies showed that metastatic tumor cells migrate individually [154]. However, in humans, seeding requires the joint action of a cluster of cancer cells moving together, which brings EMT into the picture [155]. EMT program is believed to be a spectrum of transitional stages between the epithelial and mesenchymal phenotypes, in contrast to a progression that includes a binary choice between full-epithelial and full-mesenchymal phenotypes [156].

In recent years, there has been a vital debate on whether EMT features a central role in cancer metastasis and resistance to chemotherapy [157]. Some studies in pancreatic and lung cancers showed that EMT is not essential for metastasis, but it does contribute to chemoresistance. More evidence is required to completely elucidate the role of EMT in cancer progression and the metastatic process [158-160].

Another important thing that researchers are looking at is ECM. ECM is a dynamic and complex system that is composed of a wide spectrum of matrikines and cells that take part in invasion and metastasis [161].

Our deep understanding of the dynamics of this hallmark will help us identify targets for molecular therapies which will halt or possibly reverse cancer growth and metastasis.

Reprogramming of Energy Metabolism

Abnormally high metabolic rates by cancer cells alter anti- tumor immunity by changing TME in the metabolic mechanism of glycolysis or amino acid metabolism. There are studies discussing the crosstalk between energy reprogramming in cancer cells and its association with antitumor immunity, and therefore suggest intervention of cancer metabolic agents provide an add-on benefit to cancer immunotherapy [162].

Glycolysis and Lactate Production

The Warburg effect shows that tumors and cancer cells have increased rates of glucose uptake and lactate production, even in the presence of sufficient oxygen and low rate of oxidative phosphorylation [163]. Metabolic reprogramming in tumor cells causes changes in TME by competing metabolic environment in neighboring T cells, that lead to T cell metabolic exhaustion. Notably, several clinical studies have revealed that aerobic glycolytic activities in humans is negatively correlated with intrinsic antitumor immunity. For example, LDHA (lactate dehydrogenase A)-associated lactic acid accumulation in melanomas inhibits tumor surveillance by T and NK cells, and LDHA mediated lactate production suppresses IFN-γ expression in both tumor-infiltrating and immune evasion murine models [164]. Pyruvate kinase muscle isozyme M2 (PKM2) has a crucial role in sustaining nutrients demands in cancer cell proliferation [165]. Recently, PKM2 has been reported to promote PD-L1 (programmed cell death 1 ligand 1) expression in tumor, and PKM2 activators might synergize with PD-1 (programmed cell death 1)/PD-L1 checkpoint inhibitors to provide suppressive roles to tumor immune escape [166].

Amino Acids Metabolism

Tryptophan (Trp) and arginine (Arg) amino acids are considered to provide key nutrients in TME. Trp attenuates antitumor immunity in primary tumors and the neighboring tumor lymph nodes and Arg catabolism has been linked to suppression of antitumor immunity.

Indoleamine 2,3-dioxygenase 1 (IDO1) enzyme is a rate-limiting enzyme in the metabolism of Trp in the peripheral tissues and IDOI inhibitors inhibit the first step of Trp catabolism [167]. IDO1 is overexpressed in human cancer cells, suppresses effector T cell function, and promotes regulatory T cells [168]. Tumor or stromal cells in malignant lesions catabolizing Trp and/or Arg suppress CD8+ effector T cells and stabilize Treg cells to protect tumor cells [169].

PD-1 ligation and activation impairs metabolic reprogramming, including glycolysis and amino acid metabolism in T cells by inducing the expression of carnitine palmityl transferase 1A (CPT1A), a rate limiting enzyme of the fatty acid oxidation (FAO) pathway, and conversely, CTLA-4 inhibits glycolysis without augmenting FAO [170]. Arginine inhibitor, INCB001158 combined with immune checkpoint inhibitor pembrolizumab, is being studied in advanced or metastatic solid tumors (ClinicalTrials.gov Identifier: NCT02903914). Epacadostat, an IDO1 inhibitor, is being studied in combination with pembrolizumab in patients with metastatic and/or locally advanced sarcoma (NCT03414229). Anti-IDO-1 agent (LY3381916) is also tested in combination with anti- PD-L1 checkpoint antibody (LY3300054) in solid tumors (NCT03343613). Additionally, a phase 2 study is ongoing to evaluate the activity of PD-1 inhibitor, nivolumab alone with and without IDO-inhibitor, BMS-986205, in patients with recurrent or persistent endometrial carcinoma or endometrial carcinosarcoma (NCT04106414). Given great and extensive interests of IDO inhibitors and other metabolic agents, it is expected there will be more clinical studies underway in addressing metabolic intervention in TME to aid on immunotherapy.

Evading Immune Suppression

Evading antitumor immunity plays a major role in tumor progression and survival and must be considered as one of the hallmarks of cancer. Tumor escapes immune destruction by several mechanisms. TGFβ plays a significant role in inhibiting T helper cell differentiation and promoting antitumor immunity [171,172]. Tumor derived factors convert immature myeloid cells into myeloid derived suppressor cells (MDSC) that suppress antitumor immune response [2]. Tumor recruits and educate immune cells such as NK cells, regulatory T cells, dendritic cells, granulocytes, macrophages, and MDSC thereby creating permissive microenvironment [173]. Tumor modulates spleen and bone marrow via exosomes creating permissive macroenvironment [173]. Tumor exosomes not only impair T cell function, but also produce monocytic MDSC that impairs tumor recognition by immune cells [39]. ECM can impair antigen presenting cells and inhibit T-cell activation suppressing T-cell function against tumor [174]. Commensal microbiota is also reported to have a role in impairing antitumor immunity [40].

In this era of immunotherapy, several studies are underway to improve anticancer therapy based on these mechanisms of evading immune suppression. Commensal microbiota was reported to have a role in improving anti-tumor response to immunotherapy and chemotherapy in extraintestinal tumors [2]. Blocking TGFβ signaling could potentially promote antitumor immunity [171], which is proved in advanced colorectal cancer using TGFβ inhibitors [172].

Conclusions

In conclusion, we summarized the hallmarks of cancer. Pro-survival autophagy is described as a new hallmark of cancer given its important role in tumorigenesis and potentially an anti-cancer therapeutic target. The bidirectional interaction between a cancer cell and microenvironment as well as macroenvironment is key for a cancer cell to develop, survive, progress, and invade. In addition, cancer epigenetics, genome instability and mutation play a major role in enabling cells to acquire the hallmarks of cancer. Despite the advanced understanding, we have so far on hallmarks of cancer, there is much more to uncover in this field of research. Future research in this field is necessary to develop better ways to treat cancer.


References

  1. Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell. 2011, 144:646-74. 10.1016/j.cell.2011.02.013
  2. Rutkowski MR, Svoronos N, Perales-Puchalt A, Conejo-Garcia JR: The tumor macroenvironment: Cancer-promoting networks beyond tumor beds. Adv Cancer Res. 2015, 128:235-62. 10.1016/bs.acr.2015.04.011
  3. Das CK, Banerjee I, Mandal M: Pro-survival autophagy: an emerging candidate of tumor progression through maintaining hallmarks of cancer. Semin Cancer Biol. 2020, 66:59-74. 10.1016/j.semcancer.2019.08.020
  4. Kim MJ, Woo SJ, Yoon CH, et al.: Involvement of autophagy in oncogenic K-Ras-induced malignant cell transformation. J Biol Chem. 2011, 286:12924-32. 10.1074/jbc.M110.138958
  5. Tan Q, Wang M, Yu M, Zhang J, Bristow RG, Hill RP, Tannock IF: Role of autophagy as a survival mechanism for hypoxic cells in tumors. Neoplasia. 2016, 18:347-55. 10.1016/j.neo.2016.04.003
  6. Guo JY, White E: Autophagy is required for mitochondrial function, lipid metabolism, growth, and fate of KRAS(G12D)-driven lung tumors. Autophagy. 2013, 9:1636-8. 10.4161/auto.26123
  7. Rabinowitz JD, White E: Autophagy and metabolism. Science. 2010, 330:1344-8. 10.1126/science.1193497
  8. Yang S, Wang X, Contino G, et al.: Pancreatic cancers require autophagy for tumor growth. Genes Dev. 2011, 25:717-29. 10.1101/gad.2016111
  9. Takamura A, Komatsu M, Hara T, et al.: Autophagy-deficient mice develop multiple liver tumors. Genes Dev. 2011, 25:795-800. 10.1101/gad.2016211
  10. Huang T, Song X, Yang Y, et al.: Autophagy and hallmarks of cancer. Crit Rev Oncog. 2018, 23:247-67. 10.1615/CritRevOncog.2018027913
  11. Shen H, Yin L, Deng G, et al.: Knockdown of beclin-1 impairs epithelial-mesenchymal transition of colon cancer cells. J Cell Biochem. 2018, 119:7022-31. 10.1002/jcb.26912
  12. Kim YH, Baek SH, Kim EK, et al.: Uncoordinated 51-like kinase 2 signaling pathway regulates epithelial-mesenchymal transition in A549 lung cancer cells. FEBS Lett. 2016, 590:1365-74. 10.1002/1873-3468.12172
  13. Avivar-Valderas A, Salas E, Bobrovnikova-Marjon E, Diehl JA, Nagi C, Debnath J, Aguirre-Ghiso JA: PERK integrates autophagy and oxidative stress responses to promote survival during extracellular matrix detachment. Mol Cell Biol. 2011, 31:3616-29. 10.1128/MCB.05164-11
  14. Sun L, Li T, Wei Q, Zhang Y, Jia X, Wan Z, Han L: Upregulation of BNIP3 mediated by ERK/HIF-1α pathway induces autophagy and contributes to anoikis resistance of hepatocellular carcinoma cells. Future Oncol. 2014, 10:1387-98. 10.2217/fon.14.70
  15. Fu XT, Shi YH, Zhou J, et al.: MicroRNA-30a suppresses autophagy-mediated anoikis resistance and metastasis in hepatocellular carcinoma. Cancer Lett. 2018, 412:108-17. 10.1016/j.canlet.2017.10.012
  16. Talukdar S, Pradhan AK, Bhoopathi P, et al.: Regulation of protective autophagy in anoikis-resistant glioma stem cells by SDCBP/MDA-9/Syntenin. Autophagy. 2018, 14:1845-6. 10.1080/15548627.2018.1502564
  17. Chaterjee M, van Golen KL: Breast cancer stem cells survive periods of farnesyl-transferase inhibitor-induced dormancy by undergoing autophagy. Bone Marrow Res. 2011, 2011:362938. 10.1155/2011/362938
  18. Sanchez CG, Penfornis P, Oskowitz AZ, et al.: Activation of autophagy in mesenchymal stem cells provides tumor stromal support. Carcinogenesis. 2011, 32:964-72. 10.1093/carcin/bgr029
  19. Zhu H, Wang D, Liu Y, et al.: Role of the Hypoxia-inducible factor-1 alpha induced autophagy in the conversion of non-stem pancreatic cancer cells into CD133+ pancreatic cancer stem-like cells. Cancer Cell Int. 2013, 13:119. 10.1186/1475-2867-13-119
  20. Ojha R, Jha V, Singh SK, Bhattacharyya S: Autophagy inhibition suppresses the tumorigenic potential of cancer stem cell enriched side population in bladder cancer. Biochim Biophys Acta. 2014, 1842:2073-86. 10.1016/j.bbadis.2014.07.007
  21. Chen K, Shi W: Autophagy regulates resistance of non-small cell lung cancer cells to paclitaxel. Tumour Biol. 2016, 37:10539-44. 10.1007/s13277-016-4929-x
  22. Gupta A, Roy S, Lazar AJ, et al.: Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST). Proc Natl Acad Sci U S A. 2010, 107:14333-8. 10.1073/pnas.1000248107
  23. Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B: The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol. 2010, 11:329-41. 10.1038/nrm2882
  24. Ojha R, Singh SK, Bhattacharyya S, Dhanda RS, Rakha A, Mandal AK, Jha V: Inhibition of grade dependent autophagy in urothelial carcinoma increases cell death under nutritional limiting condition and potentiates the cytotoxicity of chemotherapeutic agent. J Urol. 2014, 191:1889-98. 10.1016/j.juro.2014.01.006
  25. Shao S, Li S, Qin Y, et al.: Spautin-1, a novel autophagy inhibitor, enhances imatinib-induced apoptosis in chronic myeloid leukemia. Int J Oncol. 2014, 44:1661-8. 10.3892/ijo.2014.2313
  26. Egan DF, Chun MG, Vamos M, et al.: Small molecule inhibition of the autophagy kinase ULK1 and identification of ULK1 substrates. Mol Cell. 2015, 59:285-97. 10.1016/j.molcel.2015.05.031
  27. Dower CM, Bhat N, Gebru MT, Chen L, Wills CA, Miller BA, Wang HG: Targeted inhibition of ULK1 promotes apoptosis and suppresses tumor growth and metastasis in neuroblastoma. Mol Cancer Ther. 2018, 17:2365-76. 10.1158/1535-7163.MCT-18-0176
  28. Lu J, Zhu L, Zheng LP, et al.: Overexpression of ULK1 represents a potential diagnostic marker for clear cell renal carcinoma and the antitumor effects of SBI-0206965. EBioMedicine. 2018, 34:85-93. 10.1016/j.ebiom.2018.07.034
  29. Akin D, Wang SK, Habibzadegah-Tari P, et al.: A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. Autophagy. 2014, 10:2021-35. 10.4161/auto.32229
  30. Liu PF, Tsai KL, Hsu CJ, et al.: Drug repurposing screening identifies tioconazole as an Atg4 inhibitor that suppresses autophagy and sensitizes cancer cells to chemotherapy. Theranostics. 2018, 8:830-45. 10.7150/thno.22012
  31. Seitz C, Hugle M, Cristofanon S, Tchoghandjian A, Fulda S: The dual PI3K/mTOR inhibitor NVP-BEZ235 and chloroquine synergize to trigger apoptosis via mitochondrial-lysosomal cross-talk. Int J Cancer. 2013, 132:2682-93. 10.1002/ijc.27935
  32. Amaravadi RK, Winkler JD: Lys05: a new lysosomal autophagy inhibitor. Autophagy. 2012, 8:1383-4. 10.4161/auto.20958
  33. Wu YC, Wu WK, Li Y, et al.: Inhibition of macroautophagy by bafilomycin A1 lowers proliferation and induces apoptosis in colon cancer cells. Biochem Biophys Res Commun. 2009, 382:451-6. 10.1016/j.bbrc.2009.03.051
  34. Grivennikov SI, Greten FR, Karin M: Immunity, inflammation, and cancer. Cell. 2010, 140:883-99. 10.1016/j.cell.2010.01.025
  35. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A: Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 2009, 30:1073-81. 10.1093/carcin/bgp127
  36. Qian BZ, Pollard JW: Macrophage diversity enhances tumor progression and metastasis. Cell. 2010, 141:39-51. 10.1016/j.cell.2010.03.014
  37. Wu TC, Xu K, Martinek J, et al.: IL1 receptor antagonist controls transcriptional signature of inflammation in patients with metastatic breast cancer. Cancer Res. 2018, 78:5243-58. 10.1158/0008-5472.CAN-18-0413
  38. Nardinocchi L, Sonego G, Passarelli F, et al.: Interleukin-17 and interleukin-22 promote tumor progression in human nonmelanoma skin cancer. Eur J Immunol. 2015, 45:922-31. 10.1002/eji.201445052
  39. Tung KH, Ernstoff MS, Allen C, Shu S: A review of exosomes and their role in the tumor microenvironment and host-tumor “macroenvironment”. J Immunol Sci. 2019, 3:4-8. 10.29245/2578-3009/2019/1.1165
  40. Dieterich LC, Bikfalvi A: The tumor organismal environment: role in tumor development and cancer immunotherapy. Semin Cancer Biol. 2020, 65:197-206. 10.1016/j.semcancer.2019.12.021
  41. Al-Zoughbi W, Hoefler G: Tumor macroenvironment: an update. Pathobiology. 2020, 87:58-60. 10.1159/000502097
  42. Zhao CM, Hayakawa Y, Kodama Y, et al.: Denervation suppresses gastric tumorigenesis. Sci Transl Med. 2014, 6:250ra115. 10.1126/scitranslmed.3009569
  43. Zahalka AH, Arnal-Estapé A, Maryanovich M, Nakahara F, Cruz CD, Finley LW, Frenette PS: Adrenergic nerves activate an angio-metabolic switch in prostate cancer. Science. 2017, 358:321-6. 10.1126/science.aah5072
  44. Weinhold B: Epigenetics: the science of change. Environ Health Perspect. 2006, 114:A160-7. 10.1289/ehp.114-a160
  45. Dupont C, Armant DR, Brenner CA: Epigenetics: definition, mechanisms and clinical perspective. Semin Reprod Med. 2009, 27:351-7. 10.1055/s-0029-1237423
  46. Taby R, Issa JP: Cancer epigenetics. CA Cancer J Clin. 2010, 60:376-92. 10.3322/caac.20085
  47. Jones PA, Laird PW: Cancer epigenetics comes of age. Nat Genet. 1999, 21:163-7. 10.1038/5947
  48. Feinberg AP, Ohlsson R, Henikoff S: The epigenetic progenitor origin of human cancer. Nat Rev Genet. 2006, 7:21-33. 10.1038/nrg1748
  49. Kanwal R, Gupta K, Gupta S: Cancer epigenetics: an introduction. Methods Mol Biol. 2015, 1238:3-25. 10.1007/978-1-4939-1804-1_1
  50. Brait M, Sidransky D: Cancer epigenetics: above and beyond. Toxicol Mech Methods. 2011, 21:275-88. 10.3109/15376516.2011.562671
  51. ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium: Pan-cancer analysis of whole genomes. Nature. 2020, 578:82-93. 10.1038/s41586-020-1969-6
  52. Gerstung M, Jolly C, Leshchiner I, et al.: The evolutionary history of 2,658 cancers. Nature. 2020, 578:122-8. 10.1038/s41586-019-1907-7
  53. Alexandrov LB, Kim J, Haradhvala NJ, et al.: The repertoire of mutational signatures in human cancer. Nature. 2020, 578:94-101. 10.1038/s41586-020-1943-3
  54. Tubbs A, Nussenzweig A: Endogenous DNA damage as a source of genomic instability in cancer. Cell. 2017, 168:644-56. 10.1016/j.cell.2017.01.002
  55. Andor N, Maley CC, Ji HP: Genomic instability in cancer: teetering on the limit of tolerance. Cancer Res. 2017, 77:2179-85. 10.1158/0008-5472.CAN-16-1553
  56. Pua KH, Chew CL, Lane DP, et al.: Inflammation-associated genomic instability in cancer. Genome Instab Dis. 2020, 1:1-9. 10.1007/s42764-019-00006-6
  57. Platt RJ, Chen S, Zhou Y, et al.: CRISPR-Cas9 knockin mice for genome editing and cancer modeling. Cell. 2014, 159:440-55. 10.1016/j.cell.2014.09.014
  58. Lemmon MA, Schlessinger J: Cell signaling by receptor tyrosine kinases. Cell. 2010, 141:1117-34. 10.1016/j.cell.2010.06.011
  59. Witsch E, Sela M, Yarden Y: Roles for growth factors in cancer progression. Physiology (Bethesda). 2010, 25:85-101. 10.1152/physiol.00045.2009
  60. Hynes NE, MacDonald G: ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol. 2009, 21:177-84. 10.1016/j.ceb.2008.12.010
  61. Perona R: Cell signalling: growth factors and tyrosine kinase receptors. Clin Transl Oncol. 2006, 8:77-82. 10.1007/s12094-006-0162-1
  62. Cheng N, Chytil A, Shyr Y, Joly A, Moses HL: Transforming growth factor-beta signaling-deficient fibroblasts enhance hepatocyte growth factor signaling in mammary carcinoma cells to promote scattering and invasion. Mol Cancer Res. 2008, 6:1521-33. 10.1158/1541-7786.MCR-07-2203
  63. Bhowmick NA, Neilson EG, Moses HL: Stromal fibroblasts in cancer initiation and progression. Nature. 2004, 432:332-7. 10.1038/nature03096
  64. Jiang BH, Liu LZ: PI3K/PTEN signaling in angiogenesis and tumorigenesis. Adv Cancer Res. 2009, 102:19-65. 10.1016/S0065-230X(09)02002-8
  65. Yuan TL, Cantley LC: PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008, 27:5497-510. 10.1038/onc.2008.245
  66. Wertz IE, Dixit VM: Regulation of death receptor signaling by the ubiquitin system. Cell Death Differ. 2010, 17:14-24. 10.1038/cdd.2009.168
  67. Cabrita MA, Christofori G: Sprouty proteins, masterminds of receptor tyrosine kinase signaling. Angiogenesis. 2008, 11:53-62. 10.1007/s10456-008-9089-1
  68. Amit I, Citri A, Shay T, et al.: A module of negative feedback regulators defines growth factor signaling. Nat Genet. 2007, 39:503-12. 10.1038/ng1987
  69. Mosesson Y, Mills GB, Yarden Y: Derailed endocytosis: an emerging feature of cancer. Nat Rev Cancer. 2008, 8:835-50. 10.1038/nrc2521
  70. Sudarsanam S, Johnson DE: Functional consequences of mTOR inhibition. Curr Opin Drug Discov Devel. 2010, 13:31-40.
  71. O'Reilly KE, Rojo F, She QB, et al.: mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006, 66:1500-8. 10.1158/0008-5472.CAN-05-2925
  72. Collado M, Serrano M: Senescence in tumours: evidence from mice and humans. Nat Rev Cancer. 2010, 10:51-7. 10.1038/nrc2772
  73. Evan GI, d'Adda di Fagagna F: Cellular senescence: hot or what?. Curr Opin Genet Dev. 2009, 19:25-31. 10.1016/j.gde.2008.11.009
  74. Lowe SW, Cepero E, Evan G: Intrinsic tumour suppression. Nature. 2004, 432:307-15. 10.1038/nature03098
  75. Hanahan D, Weinberg RA: The hallmarks of cancer. Cell. 2000, 100:57-70. 10.1016/s0092-8674(00)81683-9
  76. Ko A, Han SY, Choi CH, et al.: Oncogene-induced senescence mediated by c-Myc requires USP10 dependent deubiquitination and stabilization of p14ARF. Cell Death Differ. 2018, 25:1050-62. 10.1038/s41418-018-0072-0
  77. Kuo ML, den Besten W, Bertwistle D, Roussel MF, Sherr CJ: N-terminal polyubiquitination and degradation of the ARF tumor suppressor. Genes Dev. 2004, 18:1862-74. 10.1101/gad.1213904
  78. Chen D, Shan J, Zhu WG, Qin J, Gu W: Transcription-independent ARF regulation in oncogenic stress-mediated p53 responses. Nature. 2010, 464:624-7. 10.1038/nature08820
  79. Ko A, Shin JY, Seo J, et al.: Acceleration of gastric tumorigenesis through MKRN1-mediated posttranslational regulation of p14ARF. J Natl Cancer Inst. 2012, 104:1660-72. 10.1093/jnci/djs424
  80. Wang X, Zha M, Zhao X, et al.: Siva1 inhibits p53 function by acting as an ARF E3 ubiquitin ligase. Nat Commun. 2013, 4:1551. 10.1038/ncomms2533
  81. Han SY, Ko A, Kitano H, et al.: Molecular chaperone Hsp90 is necessary to prevent cellular senescence via lysosomal degradation of p14ARF. Cancer Res. 2017, 77:343-54. 10.1158/0008-5472.CAN-16-0613
  82. Ko A, Han SY, Song J: Regulatory network of ARF in cancer development. Mol Cells. 2018, 41:381-9. 10.14348/molcells.2018.0100
  83. Girotti MR, Salatino M, Dalotto-Moreno T, Rabinovich GA: Sweetening the hallmarks of cancer: galectins as multifunctional mediators of tumor progression. J Exp Med. 2020, 217:20182041. 10.1084/jem.20182041
  84. Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B: A model for p53-induced apoptosis. Nature. 1997, 389:300-5. 10.1038/38525
  85. Matsui Y, Ueda S, Watanabe J, Kuwabara I, Ogawa O, Nishiyama H: Sensitizing effect of galectin-7 in urothelial cancer to cisplatin through the accumulation of intracellular reactive oxygen species. Cancer Res. 2007, 67:1212-20. 10.1158/0008-5472.CAN-06-3283
  86. Kim SW, Park KC, Jeon SM, Ohn TB, Kim TI, Kim WH, Cheon JH: Abrogation of galectin-4 expression promotes tumorigenesis in colorectal cancer. Cell Oncol (Dordr). 2013, 36:169-78. 10.1007/s13402-013-0124-x
  87. Demers M, Magnaldo T, St-Pierre Y: A novel function for galectin-7: promoting tumorigenesis by up-regulating MMP-9 gene expression. Cancer Res. 2005, 65:5205-10. 10.1158/0008-5472.CAN-05-0134
  88. Demers M, Rose AA, Grosset AA, Biron-Pain K, Gaboury L, Siegel PM, St-Pierre Y: Overexpression of galectin-7, a myoepithelial cell marker, enhances spontaneous metastasis of breast cancer cells. Am J Pathol. 2010, 176:3023-31. 10.2353/ajpath.2010.090876
  89. Campion CG, Labrie M, Lavoie G, St-Pierre Y: Expression of galectin-7 is induced in breast cancer cells by mutant p53. PLoS One. 2013, 8:e72468. 10.1371/journal.pone.0072468
  90. Grosset AA, Labrie M, Gagné D, Vladoiu MC, Gaboury L, Doucet N, St-Pierre Y: Cytosolic galectin-7 impairs p53 functions and induces chemoresistance in breast cancer cells. BMC Cancer. 2014, 14:801. 10.1186/1471-2407-14-801
  91. Stiasny A, Freier CP, Kuhn C, et al.: The involvement of E6, p53, p16, MDM2 and Gal-3 in the clinical outcome of patients with cervical cancer. Oncol Lett. 2017, 14:4467-76. 10.3892/ol.2017.6752
  92. Wang Y, Nangia-Makker P, Tait L, Balan V, Hogan V, Pienta KJ, Raz A: Regulation of prostate cancer progression by galectin-3. Am J Pathol. 2009, 174:1515-23. 10.2353/ajpath.2009.080816
  93. Santoro R, Marani M, Blandino G, Muti P, Strano S: Melatonin triggers p53Ser phosphorylation and prevents DNA damage accumulation. Oncogene. 2012, 31:2931-42. 10.1038/onc.2011.469
  94. Hill SM, Frasch T, Xiang S, Yuan L, Duplessis T, Mao L: Molecular mechanisms of melatonin anticancer effects. Integr Cancer Ther. 2009, 8:337-46. 10.1177/1534735409353332
  95. Kim CH, Yoo YM: Melatonin induces apoptotic cell death via p53 in LNCaP cells. Korean J Physiol Pharmacol. 2010, 14:365-9. 10.4196/kjpp.2010.14.6.365
  96. Coller HA, Forman JJ, Legesse-Miller A: "Myc'ed messages": myc induces transcription of E2F1 while inhibiting its translation via a microRNA polycistron. PLoS Genet. 2007, 3:e146. 10.1371/journal.pgen.0030146
  97. Woods K, Thomson JM, Hammond SM: Direct regulation of an oncogenic micro-RNA cluster by E2F transcription factors. J Biol Chem. 2007, 282:2130-4. 10.1074/jbc.C600252200
  98. He L, Thomson JM, Hemann MT, et al.: A microRNA polycistron as a potential human oncogene. Nature. 2005, 435:828-33. 10.1038/nature03552
  99. Gillies JK, Lorimer IA: Regulation of p27Kip1 by miRNA 221/222 in glioblastoma. Cell Cycle. 2007, 6:2005-9. 10.4161/cc.6.16.4526
  100. le Sage C, Nagel R, Egan DA, et al.: Regulation of the p27(Kip1) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation. EMBO J. 2007, 26:3699-708. 10.1038/sj.emboj.7601790
  101. Du B, Wang Z, Zhang X, Feng S, Wang G, He J, Zhang B: MicroRNA-545 suppresses cell proliferation by targeting cyclin D1 and CDK4 in lung cancer cells. PLoS One. 2014, 9:e88022. 10.1371/journal.pone.0088022
  102. de Oliveira JC, Oliveira LC, Mathias C, et al.: Long non-coding RNAs in cancer: another layer of complexity. J Gene Med. 2019, 21:e3065. 10.1002/jgm.3065
  103. Du Y, Kong G, You X, et al.: Elevation of highly up-regulated in liver cancer (HULC) by hepatitis B virus X protein promotes hepatoma cell proliferation via down-regulating p18. J Biol Chem. 2012, 287:26302-11. 10.1074/jbc.M112.342113
  104. Tang SS, Zheng BY, Xiong XD: LincRNA-p21: implications in human diseases. Int J Mol Sci. 2015, 16:18732-40. 10.3390/ijms160818732
  105. Liu J, Xing Y, Xu L, Chen W, Cao W, Zhang C: Decreased expression of pseudogene PTENP1 promotes malignant behaviours and is associated with the poor survival of patients with HNSCC. Sci Rep. 2017, 7:41179. 10.1038/srep41179
  106. Yang F, Zhang L, Huo XS, et al.: Long noncoding RNA high expression in hepatocellular carcinoma facilitates tumor growth through enhancer of zeste homolog 2 in humans. Hepatology. 2011, 54:1679-89. 10.1002/hep.24563
  107. Naemura M, Murasaki C, Inoue Y, Okamoto H, Kotake Y: Long noncoding RNA Anril regulates proliferation of non-small cell lung cancer and cervical. Cancer Cells Anticancer Res. 2015, 35:5377-82.
  108. Jacobson MD, Weil M, Raff MC: Programmed cell death in animal development. Cell. 1997, 88:347-54. 10.1016/s0092-8674(00)81873-5
  109. Zörnig M, Hueber A, Baum W, Evan G: Apoptosis regulators and their role in tumorigenesis. Biochim Biophys Acta. 2001, 1551:1. 10.1016/s0304-419x(01)00031-2
  110. Danial NN, Korsmeyer SJ: Cell death: critical control points. Cell. 2004, 116:205-19. 10.1016/s0092-8674(04)00046-7
  111. Brenner C, Cadiou H, Vieira HL, et al.: Bcl-2 and Bax regulate the channel activity of the mitochondrial adenine nucleotide translocator. Oncogene. 2000, 19:329-36. 10.1038/sj.onc.1203298
  112. Chen ZX, Pervaiz S: Bcl-2 induces pro-oxidant state by engaging mitochondrial respiration in tumor cells. Cell Death Differ. 2007, 14:1617-27. 10.1038/sj.cdd.4402165
  113. Huang HL, Fang LW, Lu SP, Chou CK, Luh TY, Lai MZ: DNA-damaging reagents induce apoptosis through reactive oxygen species-dependent Fas aggregation. Oncogene. 2003, 22:8168-77. 10.1038/sj.onc.1206979
  114. Oda E, Ohki R, Murasawa H, et al.: Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science. 2000, 288:1053-8. 10.1126/science.288.5468.1053
  115. Schuler M, Bossy-Wetzel E, Goldstein JC, Fitzgerald P, Green DR: p53 induces apoptosis by caspase activation through mitochondrial cytochrome c release. J Biol Chem. 2000, 275:7337-42. 10.1074/jbc.275.10.7337
  116. Chipuk JE, Maurer U, Green DR, Schuler M: Pharmacologic activation of p53 elicits Bax-dependent apoptosis in the absence of transcription. Cancer Cell. 2003, 4:371-81. 10.1016/s1535-6108(03)00272-1
  117. Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M, Green DR: Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science. 2004, 303:1010-4. 10.1126/science.1092734
  118. Blasco MA: Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet. 2005, 6:611-22. 10.1038/nrg1656
  119. Shay JW, Wright WE: Hayflick, his limit, and cellular ageing. Nat Rev Mol Cell Biol. 2000, 1:72-6. 10.1038/35036093
  120. Hayflick L, Moorhead PS: The serial cultivation of human diploid cell strains. Exp Cell Res. 1961, 25:585-621. 10.1016/0014-4827(61)90192-6
  121. Reddel RR: The role of senescence and immortalization in carcinogenesis. Carcinogenesis. 2000, 21:477-84. 10.1093/carcin/21.3.477
  122. Bell RJ, Rube HT, Kreig A, et al.: The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer. Science. 2015, 348:1036-9. 10.1126/science.aab0015
  123. Chin YE, Kitagawa M, Su WC, You ZH, Iwamoto Y, Fu XY: Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21 WAF1/CIP1 mediated by STAT1. Science. 1996, 272:719-22. 10.1126/science.272.5262.719
  124. Shay JW, Bacchetti S: A survey of telomerase activity in human cancer. Eur J Cancer. 1997, 33:787-91. 10.1016/S0959-8049(97)00062-2
  125. Heaphy CM, Subhawong AP, Hong SM, et al.: Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes. Am J Pathol. 2011, 179:1608-15. 10.1016/j.ajpath.2011.06.018
  126. Jafri MA, Ansari SA, Alqahtani MH, Shay JW: Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies. Genome Med. 2016, 8:69. 10.1186/s13073-016-0324-x
  127. Horn S, Figl A, Rachakonda PS, et al.: TERT promoter mutations in familial and sporadic melanoma. Science. 2013, 339:959-61. 10.1126/science.1230062
  128. Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA: Highly recurrent TERT promoter mutations in human melanoma. Science. 2013, 339:957-9. 10.1126/science.1229259
  129. Borah S, Xi L, Zaug AJ, et al.: Cancer. TERT promoter mutations and telomerase reactivation in urothelial cancer. Science. 2015, 347:1006-10. 10.1126/science.1260200
  130. Killela PJ, Reitman ZJ, Jiao Y, et al.: TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci U S A. 2013, 110:6021-6. 10.1073/pnas.1303607110
  131. Vinagre J, Almeida A, Pópulo H, et al.: Frequency of TERT promoter mutations in human cancers. Nat Commun. 2013, 4:2185. 10.1038/ncomms3185
  132. Nault JC, Mallet M, Pilati C, et al.: High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat Commun. 2013, 4:2218. 10.1038/ncomms3218
  133. Hu H, Zhang Y, Zou M, Yang S, Liang XQ: Expression of TRF1, TRF2, TIN2, TERT, KU70, and BRCA1 proteins is associated with telomere shortening and may contribute to multistage carcinogenesis of gastric cancer. J Cancer Res Clin Oncol. 2010, 136:1407-14. 10.1007/s00432-010-0795-x
  134. Nonoguchi N, Ohta T, Oh JE, Kim YH, Kleihues P, Ohgaki H: TERT promoter mutations in primary and secondary glioblastomas. Acta Neuropathol. 2013, 126:931-7. 10.1007/s00401-013-1163-0
  135. Wai LK: Telomeres, telomerase, and tumorigenesis -- a review. MedGenMed. 2004, 6:19.
  136. Hirashima K, Migita T, Sato S, Muramatsu Y, Ishikawa Y, Seimiya H: Telomere length influences cancer cell differentiation in vivo. Mol Cell Biol. 2013, 33:2988-95. 10.1128/MCB.00136-13
  137. Derycke LD, Bracke ME: N-cadherin in the spotlight of cell-cell adhesion, differentiation, embryogenesis, invasion and signalling. Int J Dev Biol. 2004, 48:463-76. 10.1387/ijdb.041793ld
  138. McDonald KL, McDonnell J, Muntoni A, et al.: Presence of alternative lengthening of telomeres mechanism in patients with glioblastoma identifies a less aggressive tumor type with longer survival. J Neuropathol Exp Neurol. 2010, 69:729-36. 10.1097/NEN.0b013e3181e576cf
  139. Oh BK, Kim YJ, Park C, Park YN: Up-regulation of telomere-binding proteins, TRF1, TRF2, and TIN2 is related to telomere shortening during human multistep hepatocarcinogenesis. Am J Pathol. 2005, 166:73-80. 10.1016/S0002-9440(10)62233-X
  140. Gay-Bellile M, Romero P, Cayre A, et al.: ERCC1 and telomere status in breast tumours treated with neoadjuvant chemotherapy and their association with patient prognosis. J Pathol Clin Res. 2016, 2:234-46. 10.1002/cjp2.52
  141. Butler KS, Hines WC, Heaphy CM, Griffith JK: Coordinate regulation between expression levels of telomere-binding proteins and telomere length in breast carcinomas. Cancer Med. 2012, 1:165-75. 10.1002/cam4.14
  142. Huang EE, Tedone E, O'Hara R, et al.: The maintenance of telomere length in CD28+ T cells during T lymphocyte stimulation. Sci Rep. 2017, 7:6785. 10.1038/s41598-017-05174-7
  143. Artandi SE, Chang S, Lee SL, Alson S, Gottlieb GJ, Chin L, DePinho RA: Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature. 2000, 406:641-5. 10.1038/35020592
  144. Meeker AK, Hicks JL, Platz EA, March GE, Bennett CJ, Delannoy MJ, De Marzo AM: Telomere shortening is an early somatic DNA alteration in human prostate tumorigenesis. Cancer Res. 2002, 62:6405-9.
  145. Okamoto K, Seimiya H: Revisiting telomere shortening in cancer. Cells. 2019, 8:107. 10.3390/cells8020107
  146. Hahn WC, Weinberg RA: Rules for making human tumor cells. N Engl J Med. 2002, 347:1593-603. 10.1056/NEJMra021902
  147. Blasco MA, Lee HW, Hande MP, et al.: Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell. 1997, 91:25-34. 10.1016/s0092-8674(01)80006-4
  148. Nishida N, Yano H, Nishida T, Kamura T, Kojiro M: Angiogenesis in cancer. Vasc Health Risk Manag. 2006, 2:213-9. 10.2147/vhrm.2006.2.3.213
  149. Tonini T, Rossi F, Claudio PP: Molecular basis of angiogenesis and cancer. Oncogene. 2003, 22:6549-56. 10.1038/sj.onc.1206816
  150. Fouad YA, Aanei C: Revisiting the hallmarks of cancer. Am J Cancer Res. 2017, 7:1016-36.
  151. Rajabi M, Mousa SA: The role of angiogenesis in cancer treatment. Biomedicines. 2017, 54:34. 10.3390/biomedicines5020034
  152. Carmeliet P: Angiogenesis in life, disease and medicine. Nature. 2005, 438:932-6. 10.1038/nature04478
  153. Talmadge JE, Fidler IJ: AACR centennial series: the biology of cancer metastasis: historical perspective. Cancer Res. 2010, 70:5649-69. 10.1158/0008-5472.CAN-10-1040
  154. Clark AG, Vignjevic DM: Modes of cancer cell invasion and the role of the microenvironment. Curr Opin Cell Biol. 2015, 36:13-22. 10.1016/j.ceb.2015.06.004
  155. Ye X, Weinberg RA: Epithelial-mesenchymal plasticity: a central regulator of cancer progression. Trends Cell Biol. 2015, 25:675-86. 10.1016/j.tcb.2015.07.012
  156. Nieto MA, Huang RY, Jackson RA, Thiery JP: EMT. Cell. 2016, 166:21-45. 10.1016/j.cell.2016.06.028
  157. De Craene B, Berx G: Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013, 13:97-110. 10.1038/nrc3447
  158. Fischer KR, Durrans A, Lee S, et al.: Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature. 2015, 527:472-6. 10.1038/nature15748
  159. Zheng X, Carstens JL, Kim J, et al.: Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature. 2015, 527:525-30. 10.1038/nature16064
  160. Diepenbruck M, Christofori G: Epithelial-mesenchymal transition (EMT) and metastasis: yes, no, maybe?. Curr Opin Cell Biol. 2016, 43:7-13. 10.1016/j.ceb.2016.06.002
  161. Lu P, Weaver VM, Werb Z: The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol. 2012, 196:395-406. 10.1083/jcb.201102147
  162. Li X, Wenes M, Romero P, Huang SC, Fendt SM, Ho PC: Navigating metabolic pathways to enhance antitumour immunity and immunotherapy. Nat Rev Clin Oncol. 2019, 16:425-41. 10.1038/s41571-019-0203-7
  163. Warburg O: The metabolism of carcinoma cells. Cancer Res. 1925, 9:148-63. 10.1158/jcr.1925.148
  164. Brand A, Singer K, Koehl GE, et al.: LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 2016, 24:657-71. 10.1016/j.cmet.2016.08.011
  165. Dong G, Mao Q, Xia W, Xu Y, Wang J, Xu L, Jiang F: PKM2 and cancer: the function of PKM2 beyond glycolysis. Oncol Lett. 2016, 11:1980-6. 10.3892/ol.2016.4168
  166. Palsson-McDermott EM, Dyck L, Zasłona Z, Menon D, McGettrick AF, Mills KH, O'Neill LA: Pyruvate kinase M2 is required for the expression of the immune checkpoint PD-L1 in immune cells and tumors. Front Immunol. 2017, 8:1300. 10.3389/fimmu.2017.01300
  167. Lemos H, Huang L, Prendergast GC, Mellor AL: Immune control by amino acid catabolism during tumorigenesis and therapy. Nat Rev Cancer. 2019, 19:162-75. 10.1038/s41568-019-0106-z
  168. Komiya T, Huang CH: Updates in the clinical development of epacadostat and other indoleamine 2,3-dioxygenase 1 inhibitors (IDO1) for human cancers. Front Oncol. 2018, 8:423. 10.3389/fonc.2018.00423
  169. Platten M, Wick W, Van den Eynde BJ: Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. Cancer Res. 2012, 72:5435-40. 10.1158/0008-5472.CAN-12-0569
  170. Patsoukis N, Bardhan K, Chatterjee P, et al.: PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun. 2015, 6:6692. 10.1038/ncomms7692
  171. Gorelik L, Flavell RA: Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med. 2001, 7:1118-22. 10.1038/nm1001-1118
  172. Tauriello DV, Palomo-Ponce S, Stork D, et al.: TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature. 2018, 554:538-43. 10.1038/nature25492
  173. Becker JC: Tumor-educated myeloid cells: impact the micro- and macroenvironment. Exp Dermatol. 2014, 23:157-8. 10.1111/exd.12241
  174. Pickup MW, Mouw JK, Weaver VM: The extracellular matrix modulates the hallmarks of cancer. EMBO Rep. 2014, 15:1243-53. 10.15252/embr.201439246

Review article
peer-reviewed

An Update to Hallmarks of Cancer


Author Information

Swapna Ravi Corresponding Author

Department of Medicine, St. Luke's Hospital, Duluth, USA

Antonio M. Alencar Jr.

Department of Medical Oncology, Hospital Universitário da Universidade Federal do Maranhão, Hospital São Domingos, São Luís, BRA

Jemma Arakelyan

Department of Oncology/Solid Tumors, Yerevan State Medical University, Hematology Center After Prof. R. Yeolyan, Yerevan, ARM

Weihao Xu

Department of Business Development, Harbour BioMed, Boston, USA

Roberta Stauber

Department of Oncology, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, BRA

Cheng-Chi I. Wang

Department of Research and Development, Beltie Bio, Inc, San Diego, USA

Ruzanna Papyan

Department of Pediatric Oncology and Hematology, Yerevan State Medical University, Pediatric Center and Blood Disorders Center of Armenia, Yerevan, ARM

Narine Ghazaryan

Department of Molecular Biology, L.A. Orbeli Institute of Physiology National Academy of Sciences, Republic of Armenia (NAS RA) Hematology Center After Prof. R. Yeolyan, Yerevan, ARM

Rosalina M. Pereira

Department of Neurology, University of Texas Southwestern Medical Center, Dallas, USA


Ethics Statement and Conflict of Interest Disclosures

Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.



Review article
peer-reviewed

An Update to Hallmarks of Cancer


Figures etc.

SIQ
9.1
RATED BY 2 READERS
CONTRIBUTE RATING

Scholarly Impact Quotient™ (SIQ™) is our unique post-publication peer review rating process. Learn more here.