Int J Clin Exp Med 2019;12(1):132-157 www.ijcem.com /ISSN:1940-5901/IJCEM0072581

Review Article All hallmarks lead to diversity

Alaa Alkhazraji1, Mohamed Elgamal2, Shi Hui Ang3, Velizar Shivarov4

1Department of Internal Medicine, Zayed Military Hospital, Abu Dhabi, United Arab Emirates; 2Department of Or- thopedics, Alexandria University Hospital, Alexandria, Egypt; 3GIC Private Limited, Singapore, Singapore; 4Depart- ment of CIinical Hematology and Laboratory of Clinical Immunology, Sofiamed University Hospital, Sofia, Bulgaria Received January 7, 2018; Accepted October 11, 2018; Epub January 15, 2019; Published January 30, 2019

Abstract: The concept of cancer hallmarks is considered a major generalization of the principles of cancer biol- ogy. Many refinements of this concept were proposed based on the novel findings regarding the molecular and cellular features of cancer cells elucidated since 2000. Furthermore, in the last decade the rapid development of high-throughput omics technologies provided unprecedented insights into the evolutionary dynamics of populations. Here, we proposed an extension of the cancer hallmarks concept based on the recent refinements of our understating of evolutionary mechanisms underlying cancer initiation and progression.

Keywords: Cancer, hallmarks, evolution, genetics, epigenetics, diversity

Introduction nal Kuhnian view. The second paper on hall- marks shows that Hanahan and Weinberg keep The two landmark papers by Douglas Hanahan their views open for novel discoveries and and Robert Weinberg on the hallmarks of can- accept that many currently unexplainable pro- cer summarized over a century of extensive cesses and phenomena exist [1]. research on cancer biology [1, 2]. Probably the acceptance of this theoretical generalization by This report neither intends to answer any open the scientific community went far beyond au- issue in cancer biology nor refutes the original thors’ initial expectations and intentions. Us- work by Hanahan and Weinberg. It is rather an ually widely accepted, this concept also faced attempt to present and justify our view on the some serious criticism being considered a logi- broad definition of cancer hallmarks and their cal continuation of the so called somatic theory interrelation. We acknowledge most of the defi- of cancer and not being able to identify unique nitions of Hanahan and Weinberg. We, however, cancer features [3]. Some reports attempted to accept a strictly Darwinian view on cancer redefine and expand the cancer hallmarks con- development as proposed initially by Peter cept emphasizing different aspects of cancer Nowell [10], i.e., through gradual selection and biology [4-8]. expansion of advantageous cancer cell clones with specific genetic aberrations. One of the From a purely philosophical point of view, how- absolute prerequisites [11] for this view is the ever, one can consider the cancer hallmarks as ability of cancer cell populations to generate an obvious classical paradigm or disciplinary and sustain features that can be passed to matrix as proposed by the American philoso- daughter cells through genetic or epigenetic pher Thomas Kuhn in his influential treatise mechanisms [12-14]. Therefore, we propose The Structure of Scientific Revolutions [9]. that extreme proneness to diversification (or Taking this view, cancer hallmarks indeed rep- heterogeneity generation) of cancer cell popula- resent a conceptual framework, which attempts tion is its main hallmark allowing for an efficient to explain the already known natural phenome- cancer cell population evolution under the natu- na of cancer biology. However, the cancer hall- ral selection of the organisms’ various microen- marks story and its proponents do not function vironments as well as under the conditions of as a true normal science according to the origi- anticancer therapy. In order to propose a logical Cancer hallmarks review extension of the concept of cancer hallmarks studied example of intertumor heterogeneity, is from an evolutionary perspective, we defined subdivided into five subtypes - luminal A, lumi- the following hallmarks: (1) Extensive genomic nal B, HER2-positive, triple negative and nor- and epigenetic diversification; (2) Sustaining mal breast-like subtype [15]. However, NGS proliferative signaling; (3) Evasion of tumor studies show that many tumors and their sub- growth suppressors; (4) Enabling replicative types are phenotypically similar but can be immortality; (5) Resistance to cell death; (6) genetically diverse. Sequencing studies show Modulation of modulatory microenvironment; that very few were observed in more (7) Enabling and adaptive metabolism; and (8) than 5-10% of tumors of a particular tissue Metastatic potential and cellular plasticity. type [16]. Furthermore, efforts to define tumor subgroups based on specific mutations may Below we outlined the major characteristics of also be confounded by epistasis, which implies these hallmarks and explained in brief how all the action of one gene on another: for instance, hallmarks contribute to the extensive genomic in acute myeloid leukemia (AML), NPM1 muta- and epigenetic diversification of cancer cell tions confer a favorable prognosis only in the populations. Our view on the interrelation of presence of a co-occurring IDH1 or IDH2 muta- cancer hallmarks is schematically represented tion [17]. in Figure 1. Another line of evidence for the central role of Extensive genomic and epigenetic diversifica- generation of tumor heterogeneity and through tion extensive genetic and epigenetic diversification is that the order of mutations matters for the In 2011, Hanahan and Weinberg [1] proposed acquisition of tumor phenotype at least in some genomic instability as an enabling cancer hall- mark. We further develop the idea of this hall- instances. The classical example is the ordered mark and consider genomic instability as a pre- acquisition of mutations in colon cancer. The requisite for the generation of clonal he- initial APC gene mutations are usually followed terogeneity within the tumor tissue. Besides, by mutations in proliferation controlling genes we propose that epigenetic mechanisms also such as KRAS, NRAS, AKT1 and the final step is account for heritable diversity within the tumor. usually the loss of tumor suppressor TP53 [18]. These heritable genomic and epigenetic diver- The acquisition of mutations in some genes sities contribute to the establishment of pheno- can help the appearance of specific mutations typic heterogeneity. Therefore, we prioritize this in other genes. DNA methyltransferase 3A hallmark as the central (very core) hallmark of (DNMT3A) gene mutations are frequently the cancer. Furthermore, at least partly all other first genetic event in leukemia affecting hema- hallmarks can contribute to further diversifica- topoietic stem cells and are frequently followed tion of the tumor tissue and ensure the “build- by the acquisition of indel mutations in NPM1 ing material” for the clonal evolution of cancer and FLT3 genes [19]. Furthermore, in the set- (Figure 1). tings in myeloproliferative diseases the initial acquisition of JAK2 V617F drives the With the advent of next generation sequencing phenotype to polycythemia vera development (NGS), large-scale sequencing efforts such as rather than to essential thrombocythemia [20]. the cancer genome (TCGA) project showed that It is therefore rational to believe that tumor cell every cancer is different and that there is no populations early on in their development fixed genomic landscape. The cancer genome develop the ability for wide-spread mutability of is characterized by heterogeneity between their genomes so that it is likely to acquire a tumor types (intertumor) and within an individu- strong driver mutation. The extreme view on al tumor (intratumor), reflecting the action of the mechanism of generation of somatic muta- the evolutionary forces of variation generation tions in cancer is the so-called mutator pheno- and natural selection. Intertumor heterogeneity type of cancer as proposed by Larry Loeb [21]. is expressed by differences between tumors of the same origin in different patients. It is repre- We, however, accept that genetic diversity in sented by different tumor subtypes with specif- cancer is not generated exclusively by pertur- ic expression features and different biological bation in DNA repair mechanisms but is estab- behavior. For example, breast cancer, a well- lished and sustained by a number of other over-

133 Int J Clin Exp Med 2019;12(1):132-157 Cancer hallmarks review lapping mechanisms as discussed further the tumor (selective proliferation of subclones below. Interestingly, human differ dra- that have a phenotypic advantage) to changes matically based on the frequency of mutations in microenvironment and/or become a tool for per cancer genome. This difference, however, triggering its metastatic potential. A clonal does not translate into the same level of varia- sweep, whereby a new clone takes over the tion in phenotypic heterogeneity. The changes entire population, replacing ancestral clones, that can compensate for the relatively lower will result in a homogenous cell population. But number of mutations in certain tumor types if not, branched tumor evolution, in which sub- might be epigenetic. In support of this idea is clones evolve in parallel, will result in extensive that acute myeloid leukemia (AML) genomes subclonal diversity [14, 33]. For example, in harbor a relatively lower number of mutations clear-cell renal cell carcinoma, sequencing mul- but up to one third of readily identifiable driver tiple biopsies from the same primary tumor mutations affect epigenetics-related genes revealed spatially separated subclones, har- (e.g. TET2, DNMT3A, IDH1/2, ASXL1, etc.) [22]. bouring heterogeneous somatic mutations and Therefore, we make no difference whether copy number events [34]. Likewise, multi-region genetic or epigenetic diversity is achieved sampling in glioblastoma documented hetero- through gradual stepwise acquisition of muta- geneous copy number events between differ- tions or some kind of an extremely active varia- ent regions of the same tumor [35]. Evidence tions generating process; the key feature for clonal diversity between primary and meta- remains only the ability of the cancer cell popu- static sites has also been demonstrated in lations to generate heritable diversification breast cancer [36] and pancreatic cancer [37, exceeding the rate in normal tissues. 38] amongst others.

Intratumor heterogeneity manifests itself in the Sustaining proliferative signaling variability of genetic and epigenetic status, gene and protein expression, morphological The proliferative advantage of cancer cell com- structure, and other features of the tumor [23]. pared to a normal cell is often considered the Such diversity is thought to develop either due principal hallmark of cancer growth. Indeed, to genetic/epigenetic disorders in tumor cells more aggressive tumors conferring worse prog- themselves or under the influence of the tumor nosis show higher proliferative capacity. We, microenvironment. Some of the epigenetic however, believe that sustained proliferative mechanisms causing tumor diversity include signaling through major signaling cascades is DNA methylation, chromatin remodeling, and not simply to ensure the presence of a bulk post-translational modification of histones [24]. tumor tissue but rather a major contributor to In fact, sequencing studies have shown that other hallmarks. In the light of our proposal that genetic abnormalities may even possibly bring the chief hallmark of cancer is the generation about epigenetic abnormalities in certain and sustaining of genomic and epigenetic het- instances [25]. Leaders in the field of epi- erogeneity we consider higher proliferation rate genetics have already proclaimed epigenetic a major contributor to it. The direct conse- dysregulation as a pivotal event in cancer quence of higher proliferation is the increased development [26, 27]. Furthermore, cancer DNA replication errors and replicative stress. metabolites and exosome secreted microRNAs As proposed recently by the Vogelstein group can play a crucial role in oncogenic reprogram- stochastic errors in DNA replication could be ming within the entire tumor [28-30]. Whether the major cause of cancer-initiating mutations genetic or epigenetic in nature, cancer-causing [39, 40]. Furthermore, cancer incidence and driving events culminate in altered gene increases with age as well as the number of expression at single cell level. Recent advances clonal DNA mutations that can initiate cancer. in single-cell RNA sequencing (RNA-Seq) con- The latter has been elegantly shown for the firmed the expectations for unprecedented hematopoietic tissue with the demonstration of intratumor diversity at transcriptomic level [31, the increased incidence of clonal hematopoie- 32]. sis of indeterminate significance with age [41- 44]. The most striking and conclusive evidence All these manifestations of variability become for the importance of DNA replication associat- the source for the evolution and adaptation of ed errors in tumorigenesis is the identification

134 Int J Clin Exp Med 2019;12(1):132-157 Cancer hallmarks review of distinct somatic mutations signatures in having a distinct set of interacting partner pro- human cancers. Among the defined 22 signa- teins [54]. Notably, it has been conclusively tures at least seven were directly related to shown that loss of RB1 is associated with DNA replication, including age related signa- increased levels of genomic instability in can- ture, AID/APOBEC associated signatures, MSH cer cell lines [55]. In a final account, the loss of related and BRCA1/BRCA2 related signature, this important checkpoint mechanism in the etc. [45-47]. Moreover, many pro-proliferative cell cycle allows the cancer cell to progress to oncogenes can cause increased replicative replication and cell division with further newly stress most notably through the collision of rep- acquired DNA aberrations, and this ultimately lication forks and transcription bubbles [48, leads to the increase of genomic instability and 49], which coupled with replicative immortality, heterogeneity of cancer. Indeed, some authors tumor suppressor genes evasion and consider increased proliferation and evasion of bypassing can contribute to genomic instability antigrowth signals a single hallmark of cancer and further genetic diversification of the tumor as they both ultimately lead to replicative stress tissue. [56].

Evading growth suppressors Enabling replicative immortality

We accept as a well-defined cancer hallmark The ultimate proliferative potential of cancer the evasion of tumor suppressor genes. To a cells has to deal with the limited DNA replica- great extent this evasion supports the concept tive potential of normal somatic cells because of constant contribution to the generation of of the constant erosion. Interestingly, extreme cancer cells diversity. For instance, the telomeres not only prevent the erosion of chro- most popular TP53 has mosomes ends and their entrance into the important roles as a sensor of DNA damage breakage-fusion-bridge (BFB) cycles that ulti- after chemicals exposure, UV irradiation, or mately lead to gross chromosomal abnormali- oncogene activation. All these insults lead to ties [57] but can also serve as off-targets of p53 stabilization and subsequent binding to endogenous mutators such as activation- the promoter regions of proapoptotic genes induced cytidine deaminase (AID) that could such as BAX and PUMA, thus leading to cell trigger apoptotic response in case of over-activ- cycle arrest, and apoptosis. TP53 is one of the ity of such mutators [58]. top ten most frequently mutated genes in human cancer leading to the loss of its DNA This resistance is elegantly bypassed by tumor protective and apoptosis induction functions cells by the well-studied overexpression of the [50]. This allows the passage of newly acquired components of the complex. Re- mutations and gross chromosome anomalies cent whole genome sequencing studies conclu- allowing for greater genomic heterogeneity in sively showed that a large proportion of can- tumor tissues. Indeed, TP53 mutated tumors cers harbor mutations in the human telomer- usually show higher genomic complexity some- ase promoter leading to its re-expression. times resulting from catastrophic genome rear- Recent data showed that telomerase re-expres- rangement events including chromothripsis sion is not only pivotal for securing [51, 52]. It has recently been shown that TP53 length in cancer cells but is rather contributing amplification is a major cancer resistance to other recognizable hallmarks [59]. The first mechanism in long-lived animals such as ele- observations suggesting that telomerase may phants [53]. play a non-canonical role in cancer were those of the unexplained need for its overexpression The other most widely studied genetic event in several mouse tumor models. Telomerase allowing evasion of anti-proliferative signaling reverse transcriptase (Tert) can suppress the is the loss of the retinoblastoma (RB1) gene. important anti-proliferative signaling of the Recent data show that pRB has a more a com- TGF-β pathway [60]. Catalytically inactive Tert plex role in cell physiology than simply regulat- can promote tumor cell proliferation through ing the cell cycle progression. This is probably induction of WNT and MYC signaling pathways achieved through the simultaneous existence [59]. Tert has also been shown to provide anti- of different monophosphorylated forms of RB apoptotic signals through activation of the

135 Int J Clin Exp Med 2019;12(1):132-157 Cancer hallmarks review

NF-kB pathway [61]. Interestingly TERT is also suppressors [67]. Even stronger evidence is the actively involved in epithelial-mesenchymal fact that BCL2 overexpression in some solid transition through TERT-mediated Wnt/b- cancers is not invariably linked to worse prog- catenin signaling, leading to the upregulation of nosis [69]. To explain these counterintuitive Snail-1 (snail family zinc finger 1) and vimentin observations that apoptosis may enhance [62]. In the light of our view on the hallmarks of tumorigenesis, a recent hypothesis has been cancer, however, most interesting are the find- coined that apoptosis may serve as a strong ings that TERT can regulate DNA damage sig- trigger for clonal selection because dying out naling through ataxia telangiectasia mutated tumor cells provide a niche for expansion of (ATM), breast cancer 1 (BRCA1), and gamma- more highly proliferating clones. A similar nor- H2A histone family, member X (γH2AX) there- mal process is observed during the thymic fore reducing the number of newly acquired development of T cells in mammals when auto- mutations during rapid DNA replication associ- reactive clones undergo rapid apoptosis provid- ated with tumor growth [63, 64]. In this way, ing sufficient space for the expansion of non- telomerase is playing a protective role for the autoreactive T cells [70]. Perturbation of this genetic integrity and propagation of a given natural competitive selection process in the advantageous cell clone. However, very recent thymus has been shown to lead to T cell lym- experimental evidence suggested that the phoma development [71, 72]. Other studies most frequent noncoding mutations across showed that the loss of the proapoptotic BH3- various cancer subtypes those in the TERT pro- only protein, PUMA, can abrogate T cell lympho- moter initially lead to bulk telomere shortening, ma development and carcinogen-induced liver and afterwards the critically short telomeres cancer in mice [73]. Finally, it has recently been cause genomic instability and telomerase up- showed that BCL2 overexpression in a mouse regulation to ensure immortalization [65]. model of myelodysplastic syndrome can im- prove macrocytic anemia and delay leukemia Resisting cell death transformation [73]. If one sticks to the classi- cal view on the role of apoptosis in cancer In the last three decades, distinct pathways for development its evasion is a major prerequisite cell death known as necrosis, apoptosis, for the sustained survival of cancer cell clones necroptosis and autophagy have been defined already having a proliferative advantage and at cellular and molecular level. The intuitive increased genomic instability [74]. On the other thinking of cancer implied that cell death hand, the non-canonical view of apoptosis through any natural mechanism should work as induction as a trigger for the proliferation of a barrier to cancer development. The classical other advantageous clones would imply that it examples of perturbation in anti-apoptotic indirectly contributes to the enhanced genera- mechanisms include deregulation of the B-cell tion of genetic heterogeneity in cancer cell pop- lymphoma-2 (BCL2) family proteins in various ulations as discussed above. cancer types [66]; the most notable example being the chromosomal translocation t(8;14) Autophagy mediated cell death has also been driving Bcl2 over-expression in follicular lym- to shown to have tumor suppressor and tumor phoma under the control of the IgH locus [67]. promoting role [75]. Interestingly, in the hypoxic We accept that in a large number of cancers tumor areas autophagy is up-regulated and perturbation of apoptosis is a hallmark of para- contributes to tumor survival [76]. A number of mount importance directly affecting cancer studies have shown that RAS-driven tumors cells survival. However, there are several lines may by autophagy addicted [77, 78]. A key of evidence that this view might indeed be an mechanism for this is probably the suppression oversimplification and that under certain cir- of p53 activation [79, 80]. Therefore, autopha- cumstances enhanced apoptotic death can gy as a tumor-promoting process is mechanisti- serve as a tumor promoting event [68]. To sup- cally linked to other hallmarks and also with port that latter idea are the observations that induction of cancer cells heterogeneity as dis- in mouse models BCL2 overexpression causes cussed above. Necrosis can also contribute to lymphomas and eventually other cancers only cancer progression through induction of tumor- with long latency and requires the acquisition promoting via the release of the of mutations in other oncogenes and tumor High mobility group 1 (HMGB1) protein from the

136 Int J Clin Exp Med 2019;12(1):132-157 Cancer hallmarks review necrotic cells [81]. Necroptosis may also have a HIF-1 pathway [84]. HIF-1 (Hypoxia-inducible significant contribution to cancer promotion at factor 1) is a transcription factor that is ubiqui- least in some instances [82]. tously expressed and is composed of two sub- units, HIF-1α and HIF-1β subunits. The HIF-1α Modulation of modulatory microenvironment subunit is regulated by O2-dependent hydroxyl- ation by prolyl hydroxylase domain protein 2 We define a broad hallmark of Modulation of (PHD2), which promotes binding of the von modulatory microenvironment. This hallmark in Hippel-Lindau protein (VHL), leading to ubiquiti- our view comprises the versatile mechanisms nation and proteasomal degradation. The through which cancer cells interact with the cel- hydroxylation reactions utilize O and α-ke- lular and acellular components of the microen- 2 toglutarate as substrates and generate CO2 vironment. Notably, cancer cells can modulate and succinate as by-products and provide a microenvironment and vice versa microenviron- direct link between metabolic state and signal- ment can directly affect tumors. Therefore, we ing to the nucleus (see below). Under hypoxic propose the inclusion within this broad hall- conditions, hydroxylation is inhibited, leading to mark such key processes as neoangiogenesis HIF-1α accumulation and its dimerization with and tumor vascularization, interaction with HIF-1β with subsequent transcriptional activa- as well as immune system tion of target genes. Thousands of genes are interaction. Notably, under certain circum- under the transcriptional regulation of HIF-1 stances the various components may act as and are implicated in virtually all other cancer cancer-promoting or anticancer mechanisms. hallmarks, including and meta- The most notable examples in this respect are static potential [85]. Most importantly, HIF-1 the tumor-promoting inflammation and the can- directly links hypoxia to inhibition of DNA dam- cer immunoediting. age response genes and contributes to genom- ic instability, including microsatellite and chro- The is a complex habi- mosomal instability [86, 87]. Hypoxia may also tat in which the cancer cells exist. It comprises drive genetic instability via the alteration of cells of hematopoietic origin, cells of mesen- transcription and translation of the DNA dam- chymal origin and non-cellular components age response and repair genes [88]. It would [83]. Cells of hematopoietic origin including ultimately promote . Furthermore, myeloid-derived cells (macrophages, neutro- hypoxia directly affects gene expression in phils, dendritic and myeloid-derived suppressor MDSCs, tumor associated macrophages and (MDSC) cells), lymphoid-derived cells (CD4+, Tregs with a net effect of suppression of antitu- CD8+ T cells, T regulatory cells (Tregs) and mor response [89]. innate lymphoid cells (ILCs)) [83]. Cells of mes- enchymal origin include mesenchymal stem As discussed in the previous hallmarks of can- cells, myofibroblasts, endothelial cells and adi- cer papers, angiogenesis is important for the pocytes. The non-cellular component includes tumor progression, invasion and eventually the extracellular matrix. It consists of proteins, metastasis. The activation of the angiogenesis glycoproteins, proteoglycans, type IV collagen, switch via HIF, VEGF, PDGF, FGF pathways leads laminin and fibronectin [83]. The diversity of to the formation of tumor neovasculature [1]. the cellular populations and the production of The immune inflammatory cells, endothelial different signals, cytokines, growth factors and cells, pericytes, and the altered extracellular the interaction of all these components pro- matrix within the tumor microenvironment play mote tumor development and angiogenesis. A a major role in angiogenesis and vascular major environmental context for the develop- remodeling [90]. Other suggested forms of new ment of this is hypoxia, which is the trigger for a vessels formation such as intussusceptive plethora of signaling pathways and regulatory angiogenesis are triggered by platelet derived networks in both cancer cells and tumor micro- -B, angiopoietins, ephrins and environment. A general line of thought is that EphB receptors [90-93]. Vasculogenic mimicry rapid tumor growth and unstable tumor vascu- is also suggested as a phenomenon by which lature render significant parts of the tumor tis- tumor cells act similar to endothelial cells and sue hypoxic. Indeed, hypoxic response is form vascular channels themselves. It was orchestrated by the relatively simple signaling demonstrated in multiple solid tumors like

137 Int J Clin Exp Med 2019;12(1):132-157 Cancer hallmarks review uveal melanoma, glioblastomas, and hepato- become altered or reduced in cancer cells. It cellular and breast carcinomas [90-94]. In the activates the NK cell by stimulating receptors light of our proposal the extreme example of present on its cell surface. This triggers apopto- the role of the tumor microenvironment on sis via TNF-α, antibody dependent complement induced genetic heterogeneity in cancer cells cytotoxicity, and cytokines release [104, 105]. came from David Scadden’s lab with the dem- Neutrophils and their contents (proteases) also onstration that Dicer1 deletion in mouse osteo- play a role in cancer growth, invasion and progenitors causes myelodysplasia and trans- metastasis. Other immune cells such as den- formation to overt acute leukemia [95]. Notably, dritic cells and macrophages bridge the innate tumor stroma can support the emergence of and the adaptive immunity serving as phago- therapeutic resistance without the need for cytes in the innate immune responses, and as genetic changes. This paracrine interplay be- antigen-presenting cells for adaptive immunity. tween tumor and stromal cells has been dem- The γδ-T cells control cancer progression by onstrated for melanoma, prostate cancer and leading to tumor lysis via secretion of IFN-γ, and lymphoma models [96-100]. antibody-dependent complement cytotoxicity [106]. The complex mammalian immune system is an indispensable player in cancer initiation, pro- There are several mechanisms through which motion, evolution and spread [101]. The inter- tumor associated inflammation can increase play between the mechanisms of the innate genetic heterogeneity at tumor initiation or pro- and adaptive immunity (including humoral and gression. It has been conclusively shown that cellular elements) is an important protective inflammatory milieu is a rich source of reactive mechanism resulting in inflammation [70]. The oxygen species (ROS) and reactive nitrogen current general paradigm in cancer immunolo- intermediates (RNI). Both of them can accumu- gy is that chronic inflammation is frequently late within the extracellular space and diffuse associated with cancer initiation and progres- into cancer cells and directly damage DNA. sion whereas acute inflammation usually has Alternatively, ROS can suppress mismatch an anti-oncogenic effect [102, 103]. The innate repair enzymes and microsatellite instability response is rapid, nonspecific against foreign [102, 107]. Various cytokines and toll-like antigens, short-lived and is not able to form an receptor (TLR) agonist can directly induce the immunological memory. It includes proteins expression of DNA damaging enzymes such as (such as cytokines complements, chemokines) Activation-induced cytidine deaminase (AID). and cells (such as natural killer (NK) cells, mast AID is naturally expressed in germinal center B cells, eosinophils, basophils, macrophages, cells which seem to be protected from its off- neutrophils, and dendritic cells). On the other targeting and collateral damage [108], which hand, the adaptive immunity is a slower res- could be overcome in the absence of p53 [109]. ponse that involves immune components more Prolonged action of the potent pro-inflammato- specific for the targeted antigens and can ry cytokine IL-6 causes AID associated translo- establish immunological memory. It includes T cations and plasmacytomas in mice [110-112]. cells, B cells and antigen presenting cells. The Ectopic expression of AID can be induced by role of the innate immunity in cancer is to ame- various microorganisms and viruses and leads liorate the inflammation caused by the tumor to rapidly growing cancers even in tissues from tissue. This process also triggers adaptive mesenchymal and epithelial origin [113-117]. immune responses for targeting cancer via more specific immune mechanisms. Comple- The main concept of the role of adaptive immu- ment activation has multifaceted role leading nity role in cancer revolves around the forma- to either activation of pathways that help in the tion of neoantigens/neoepitopes. T cell activa- eradication of cancer cells or the inhibition of tion plays a crucial role in cancer immunity. It pathways that would defend cancer cells from triggers a cascade of pathways and cytokines complement-mediated injury. production and the formation of immune check- points via the CD4+ T cells and CD8+ T cells. The genetic and epigenetic modifications can Depending on the signals present in the tumor change the cell surface markers expression. environment, these mechanisms can lead For example, the expression of MHC class I either to the killing of the cancer cells or their

138 Int J Clin Exp Med 2019;12(1):132-157 Cancer hallmarks review proliferation [118]. Programed cell death pro- support of the inclusion of such a hallmark are tein 1 (PD-1) expression by the T cells plays a the classical observations of the shift of cancer role as an immune checkpoint in cancer metabolism to the glycolytic utilization of gly- immune evasion. Another important immune cose rather than to oxidative phosphorylation checkpoint molecule is the cytotoxic T lympho- (“Warburg effect”) and the strong dependence cyte-associated antigen 4 (CTLA4). It is ex- of cancer metabolisms on glutamine utilization pressed on regulatory T cells (Tregs) but is up- [126, 127]. The major counterargument against regulated only in activated T cells.The role of the definition of altered metabolism as a hall- CTLA-4 is the modulation of T cell responses. mark of cancer is the idea that all alteration The understanding of the above signals has led might be just downstream effects of major to the discovery of immune checkpoint block- pathways altered in cancer [1]. Our current ade based therapies [119, 120]. Understanding understanding is that the “metabolic repro- the role of T cells in cancer led to the evolution gramming” in cancer serves not just to satisfy of the concept of chimeric antigen receptors the energetic demands of the this fast prolifer- (CARs) on T cells (CAR-T cells) therapy, which ating tissue but to provide versatile intermedi- has been proven to be effective in hematologi- ates for the various anabolic processes as well cal malignancies [121, 122]. as to ensure proper redox potential within the tumor tissue [128, 129]. It is also evident that The interactions between the tumor tissue and in a vast majority of cases this reprogramming immune system have been generalized by the is a result of the altered signaling through onco- model of immune editing recognizing three genes or tumor suppressor genes such as PI3K, phases of the process called Elimination, MYC and TP53 [130-134]. Equilibrium and Escape [123]. The Elimination phase involves immune cells targeting and Another emerging feature of cancer metabo- eradication of the cancer cells. The Equilibrium lism that particularly supports our idea of the phase is characterized by a dynamic balance central role of genetic and epigenetic heteroge- between cancer progression and elimination by neity of cancer is the provision of so called the immune system; here, the tumor enters a “oncometabolites”. This term refers to metabo- functional dormancy state. Finally, during the lites whose abundance increases significantly Escape phase, the immune system can no lon- in specific tumors and their emergence can be ger limit tumor growth and tumor cells evade linked to specific mutations as well as have a the immune recognition causing clinically defined role in oncogenesis [128]. Recent evi- apparent disease [124]. At this phase, the pro- dence showed that a class of enzymes known cesses through which cancer cells evade the as α-ketoglutatrate dependent dioxygenases immune system include genetic, epigenetic play pivotal roles in hypoxic cellular responses changes and selective pressure [123-125]. For and epigenetic modifications in the cells [129]. example, in certain cancers, the epigenetic This class includes enzymes such as TET silencing of JAK1 kinase leads to the tumor’s enzymes (TET1-3), histone demethylases (Ju- unresponsiveness to IFN-γ, therefore losing its monji C family), prolyl hydroxylases (PHDs), etc. antitumor immune response. The “selective α-ketoglutarate (α-KG) serves as a cofactor of pressure” on the cancer cells by the immune these enzymes undergoing concurrent oxida- system represents another escape process. It tion to succinate [135] rendering these en- includes cancer cells inhibition of apoptosis by zymes particularly sensitive to variations in the the upregulation of Bcl-XL and FLIP [123, 124]. amounts of the available α-KG. This depen- The secretion of factors such as IL-4 and IL-13 dence appears to be a potent oncogenic mech- would recruit macrophages that express TGF-β, anism. For example, some of the familial cases IL-10 and VEGF; these would have inhibitory of paragangliomas and pheochromocytomas effects on the immune cells. have biallelic loss of the succinate dehydroge- nase (SDH) gene, whereas other subsets of Enabling and adaptive metabolism these tumors as well the familial cancer syn- drome leiomyomatosis and renal cell cancer In 2010 Hanahan and Weinberg proposed an (HLRCC) have loss of the fumarate hydratase emerging hallmark, reprogramming energy (FH) resulting in low levels of α-KG resulting in metabolism [1]. The strongest arguments in global DNA methylation increase [136-140].

139 Int J Clin Exp Med 2019;12(1):132-157 Cancer hallmarks review

Another prominent example of oncometabolite mechanical stress and matrix stiffness) [151, generation is the presence of gain-of-function 152]. Specific miRNAs (e.g., miR-200) suppress mutations in isocitrate dehydrogenase 1 (IDH1) transcription of ZEB1/2 preventing EMT, ZEB1/ and 2 (IDH2) genes. Such mutations have been 2 suppress miR-200 transcription as well [153, found in gliomas, cholangiocarcinomas and 154]. After EMT and BM invasion, tumor cells AML [141, 142]. Notably, these mutations lead invade the extracellular matrix (ECM) by secre- to neomorphic catalytic activity of the enzymes tion of matrix metalloproteinases (MMP)-1, -2, leading to the preferential generation of 2-hy- and -9 and activation of the proteolytic uroki- droxyglutarate (2-HG) rather than α-KG [143]. nase-type plasminogen activator system (uPA/ 2-HG serves as a competitive inhibitor of the uPAR) [155]. α-ketoglutarate dependent dioxygenases and cause CpG islands hypermethylation [144]. Intravasation of the metastasizing cells can be 2-HG can also cause histone hypermethylation hematogenous (active or passive) or lymphatic. and block in differentiation [25, 145-147]. The process is not efficient and the blood shear forces and immune system can destroy the Taken together the examples of “oncometabo- cells in the bloodstream. It is caused by factors lites” prove that cancer-related metabolic changes must be considered as a separate similar to those involved in local invasion includ- hallmark. Besides, this hallmark has the poten- ing TGF-β, EGFR family and proteases like MMP- tial to affect at least epigenetic heterogeneity 1, -2 and -9 and activation of uPA/uPAR [155]. within the tumor either directly or in a paracrine Hematogenous intravasation depends on fashion [30, 148] and therefore can consistent- access to the vasculature and microvessel ly feed the core hallmark as proposed by our diameter, so the expression of angiogenic fac- model (Figure 1). tor VEGF correlated with the presence of liver metastasis [155, 156]. FGFs are also angiogen- Metastatic potential and cellular plasticity ic and their expression in MCF7 breast cancer increased intravasation [157]. VEGF-B can From a clinical point of view, the importance of reduce the efficacy of blood perfusion resulting the metastatic potential of cancer cells is illus- in hypoxia that stimulates invasion. It also trated by the fact that metastatic disease is the increases vessel leakiness [158]. leading cause of mortality in cancer patients [149]. The classical view on metastasis was Most of circulating tumor cells (CTCs) flowing in heralded by the 1889 Stephen Paget’s “seed the blood every day will die with less than 1% and soil” hypothesis which entails that a tumor surviving and having a chance to produce dis- cell metastasizes (“seeds”) when it reaches the tant metastasis [159]. To avoid that, CTCs appropriate soil, i.e. the organ which can sus- reform its integrin expression profile and acti- tain its growth [150]. Currently, metastasis is vate cellular signaling as the Akt signal trans- understood as a more complex process of duction pathway [160]. In avoiding the immune orchestrated molecular and biochemical even- system, the tumor cells upregulate different ts. The invasion-metastasis cascade was pro- surface protein population groups. Examples of posed to better describe the metastatic pro- such proteins are CD47 [161, 162], PD-L1 cess and it involves six steps. Below we briefly [163], and vascular cell adhesion molecule 1 outline the molecular and cellular events under- (VCAM-1) [164], which bind to macrophages to lying this cascade and finally discuss how meta- evade phagocytosis. The reduced NADPH - gen- static process contributes to the core hallmark erating enzyme present in the folate pathway is - tumor heterogeneity. increasingly relied on in order to avoid oxidative Epithelial-mesenchymal transition (EMT) en- stress [165]. Such stress can also be tolerated ables tumor cells to undergo migration and by expressing tissue factor protein on their sur- invasion by down-regulating E-cadherin, a pro- faces. These then tend to attract platelets tein involved in cell to cell adhesion, in response [166] that stimulate reversible metabolic to transcription of EMT regulating genes Snail, changes in the tumor cells and link them with Slug, Twist and zinc-finger E-box-binding 1/2 CD11b+ macrophages, thus establishing mi- (ZEB1/2) as a result of EMT signals (hypoxia, cro-clots to protect CTCs in the bloodstream growth factors, signaling pathways, metabolic, [167].

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Before extravasation CTCs get entrapped in the zation to occur the DTCs must have a tumor ini- first capillary bed they encounter. This is deter- tiating ability by residing in a cancer stem cell mined by the blood flow in the body and the ori- state [178, 179, 188] and undergo a mesen- gin of the CTCs [168]. The entrapped cells grow chymal-to-endothelial transition (MET) in order within the vessel resulting in its rupture or to restore cellular traits of the primary tumor extravasate by breaking through the vessel [189]. DTCs must create adaptive organ specif- wall. Genes involved in the process of extrava- ic colonization programs [190] that enable sation of CTCs that metastasize in lung cancer them to survive in the microenvironment of the include protein Fascin-1, invadopodia, epiregu- distant organ and to shape the supportive nich- lin and Wnt ligands [169]. Furthermore, humor- es aiding colonization [179]. al factors such as angiopoietin-like 4 (ANGPT- L4), VEGF, COX2, MMP1 and osteonectin in- It is widely accepted that most cancers exhibit crease vessel permeability [170-172]. Another some degree of intratumor heterogeneity and tumor-derived factor, SPARC, increases vascu- intrinsic genetic diversity increases the proba- lar permeability and extravasation by endothe- bility of selecting cells that are intrinsically bet- lial VCAM1 signaling [173]. Platelets that are ter in overcoming the biological and physical attached to CTCs also enhance extravasation constraints during the process of metastasis. by TGF-β and triggering EMT in the cancer cells There is growing evidence that cancer cells [174] or by secreting adenine nucleotides, behave as communities and there is coopera- which relax endothelial cell junctions. Addi- tive dynamics between tumor subpopulations tionally, tumor cells induce programmed necro- that can influence disease progression. It was sis (necroptosis) of endothelial cells, thus already recognized as early as in the 1970s increasing vascular leakiness and tumor cell [191-193] that heterogeneous subclones within extravasation and metastasis [175]. tumors possess differing capacities for growth and metastatic ability. Studies have shown evi- Extravasated cancer cells need specific condi- dence of such heterogeneity and cooperative tions in order to survive and initiate tumor dynamics contributing to greater metastatic growth in the new microenvironment they are potential. Using a xenograft zebrafish model it exposed to. They locate themselves in specific was demonstrated how an inherently invasive niches which form before the seeding of CTCs. (MITF-high) melanoma cells can cooperate with These so-called premetastatic niches are poorly invasive (MITF-low) cells. The protease formed by factors released from the primary activity and ECM deposition caused by the tumor thus providing the “soil” to the future MITF-high around the primary tumor allowed for metastasis. These factors lead to up-regulation a co-invasion with MITF-low through the solid of VEGF-A, PIGF, TGF-β and inflammatory pro- tissue surrounding the tumor site [194]. In teins S100A8/-9 [176, 177]. Tenascin C or another study, a model was developed for TGF-β released from the extravasated cancer studying subclonal competition and coopera- cell itself after arrival results in the formation of tion in Drosophila melanogaster [195]. Eich- an Ad hoc niche by amplifying Notch and Wnt enlaub et al. used a Drosophila melanogaster signaling [178, 179]. Perivascular niche form in model of epithelial tumor formation to show perivascular areas and support extravasated that overexpression of both epidermal growth cancer cells in capillary BM [180, 181]. factor receptor (EGFR) and miR-8 in wing imagi- nal disc cells results in super competitive cells Tumor dormancy occurs through two mecha- that engulf those surrounding them. These nisms, cellular and tumor mass dormancy. In super competitive cells drive tumorigenesis cellular dormancy the disseminated tumor cells and metastasis, whereas cells overexpressing (DTCs) becomes quiescent. However, during either EGFR or miR-8 alone do not [196, 197]. tumor dormancy the DTCs are kept in check by vascular insufficiency or immune system [182]. Cellular plasticity provides cells with the ability TGF-β, bone morphogenetic proteins (BMPs) to epigenetically adapt to conditions of stress and autocrine Wnt inhibition can induce dor- as well as to changes in the microenvironment. mancy in DTCs [183-185], but microenviron- Tumor cells can reversibly undergo transition ments rich in type 1 collagen or fibronectin between epithelial and mesenchymal states inhibit it [186, 187]. For the metastatic coloni- (EMT and MET). While EMT is a fundamental

141 Int J Clin Exp Med 2019;12(1):132-157 Cancer hallmarks review biological process in embryogenesis and the fitted environment of our bodies cancer wound healing, EMT activation during cancer cells rely on the universal principles of evolu- promotes disease progression and enhances tion. Early on in its ontogenesis the cancer the metastatic phenotype by providing the pre- clone has to acquire the ability to create an viously locally growing carcinomas migratory extreme diversity of genetic and epigenetic fea- and invasive capacities. These mesenchymal tures resulting in specific phenotypic variations traits cooperate to enable cancer cell to dis- that are further positively or negatively select- seminate and seed metastatic deposits [198]. ed. In fact under normal conditions our bodies However, different populations of cancer cells have constrained such a hazardous process of possess different epigenetic patterns that drive genomic diversification to the development of T these changes, and each pattern may have dif- and B lymphocytes [70]. During immune ferent clinical significance. The complexity of response the immune cells are positively EMT and metastasis lies in the heterogeneity of selected among billions of preexisting types of the population: not all cells will undergo EMT their specific receptors generated through the simultaneously, and not all cells that have random recombination of the immunoglobulin undergone EMT will successfully metastasize or T-cell receptor genes. Positively selected [199]. For instance, minimal induction of EMT cells undergo clonal expansion and prolifera- may not be sufficient to promote metastasis; tion and eventually become long lived memory however, the maximum induction of EMT may otherwise end up in stable mesenchymal can- cells. Notably, only B cells can undergo further cer cells resulting in the suboptimal outgrowth rounds of somatic hypermutation of their genes of metastases. In contrast, induction of partial and further sub-clonal selection. Obviously, the EMT could optimize tumor-initiating potential key feature of this process remains the initial while still maintaining cell plasticity (the ability generation of extreme genetic diversity. to reverse EMT process and undergo MET), thus generating more epithelial progeny which The strategy employed by cancer cells is virtu- significantly raises the odds for a successful of ally identical. The most striking example of the metastatic colony formation [198]. Cancer pro- utilization of this selection model in cancer is genitor cell characteristics, together with envi- probably the use of stereotypic B cell receptors ronmental factors, extracellular and intracellu- in certain B cell malignancies such as chronic lar signaling, and epigenetic changes all in- lymphocytic leukemia (CLL) with cognate auto- fluence the choice of whether a cell would antigens [202, 203]. The cancer cell population undergo EMT and would eventually metasta- is intrinsically prone to constant generation of size [199]. Finally, Comaills et al. [200] showed phenotypic diversity resulting from numerous how epithelial cells induced to undergo EMT epigenetic and genetic events. The elegant exhibited mitotic errors and genomic instability demonstration of clonal heterogeneity in both during the process, although the EMT process primary and metastatic cancer demonstrates was reversible upon withdrawal of the inducing that extreme heterogeneity in cancer popula- factors, the genomic changes and the hetero- tions appears selected as advantageous in geneity that resulted persisted and were heri- various microenvironments. More interestingly table. This was supported by assessing the cancer cells and microenvironments seem to prevalence of genomic instability in mesenchy- co-evolve [204]. Certain features of microenvi- mal and epithelial CTCs from breast cancer ronment and immune system may favor the patients showing higher prevalence in the mes- selection of specific cancer clones and vice enchymal lineage. versa specific clones may lead paracrine pre- Discussion formation of the tumor niche [205]. Other evi- dence that increased mutability provide evolu- In his Pulitzer-winning book The Emperor of All tionary advantage stems from the field of Maladies Dr. Mukherjee used the metaphor virology. RNA viruses (including HIV) undergo- Cancer’s life is a recapitulation of the body’s ing high levels of hypermutation of their ge- life, its existence is a pathological mirror of our nomes can acquire a pool of beneficial muta- own [201]. Here, we agreed with it and pro- tions though at the expense of generation of a posed and stated that in order to survive within large number of dead viruses [206, 207].

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radiation therapy or targeted therapy). Selected features and hallmarks within some of the cancer clones would them- selves sustain the diversifica- tion process so that they could perpetuate the cycle of cancer diversification, phenotypic va- riation and selection (Figure 2). Theoretically, such a cycle of adaptive variability can per- petuate cancer survival pro- vided a minimum of nutrients supply. Probably on the organ- ismal level this idea is evi- denced by the cross species cancer transmission in inver- tebrates and in rare cases of mammals with immune com- promise [211-216]. A model similar to ours has been pro- posed by Ye et al. based on the analysis of non-clonal ch- romosome aberrations cell line models [217]. Figure 1. Definition of eight cancer hallmarks and their interdependence. The central (core) hallmark is the ability of cancer cell populations to sustain extensive genomic and epigenetic diversity. This hallmark enables the emer- The logical counterargument gence of all others and their propagation to subsequent cell generations. against our proposal that the All other hallmarks provide competitive advantages to the cells but most sustainable ability of cancer importantly can contribute to further generation of genomic and epigenetic to diversify and survive can diversification. The outer circle symbolizes the direct and indirect interde- last forever would be that the pendence of the hallmarks. gradual mutational process would ultimately lead to can- We assume that the most important hallmark cer population extinction because of accumula- of cancer is the ability to generate and sustain tion of too many deleterious passenger muta- genetic and epigenetic diversity (Figure 1). All tions [218]. In fact is quite an other hallmarks defined by Hanahan and We- ineffective process with only 0.1% of the pre- inberg contribute to this key feature (Figure 1). malignant lesions developing a full blown can- Therefore, in our view any order of hallmarks cer [219]. Evidence to support this notion acquisition can lead to cancer and sustain its comes from mathematical modeling of the rate growth. We accept that any genetic or epigene- of mutations accumulation as well as in vitro tic event [208] or even slight genetic predispo- cell lines experiments [218, 220, 221]. Other sition [209] or transiently acting change in gene studies on the real-time evolution of small- expression [210] could potentially trigger the sized malignant breast cancer lesions suggest- acquisition of even a slightly advantageous fea- ed that a number of them can regress sponta- ture (that can be seen as an element of any neously (i.e., without apparent therapeutic given hallmark) (Figure 2). As proposed by us all intervention) [222, 223]. It is not clear whether hallmarks can contribute to the increased this is due to cancer inability to progress genetic/epigenetic diversification of the tumor because of a deleterious mutation within the tissue (Figure 1). That would inevitably lead to sole dominant clone or due to a drastic change the appearance of novel phenotypic features in the microenvironment (such as abrupt non- and hallmarks that would be put under selec- specific inflammation) rendering cancer clones tive pressure from the organism’s own mecha- unable to adapt because of lack of heritable nisms or external challenge (chemotherapy, advantageous features at least in minor sub-

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acquired gradually or abruptly through the so called punctu- ated equilibrium [14]. The ge- netic diversity necessary to provide a reasonable chance of successful adaptation mi- ght be well below the actual number of somatic mutations that a given genome can toler- ate [229, 230]. On the other hand, abruptly acting muta- tional processes such as chro- mothripsis and kataegis can completely reorganize cancer genome and reset the evolu- tionary process [231, 232]. Besides, many mutations may remain masked for a long time and become evident only under stress conditions ac- counting for rapid adaptive response after external chal- lenge as described for Hsp90 mutants in Drosophila [233]. So, even if not perpetual, the diversification and selection Figure 2. Proposed model of cancer initiation and progression. Any predis- posing or initiating event can lead to phenotypically advantageous feature(s) cycle in our view can sustain (hallmark(s)). The latter increase the genetic or epigenetic diversity through tumor growth well beyond indi- various mechanisms. This ultimately leads to further phenotypic variation vidual lifespan [14]. between the cancer clones that are subjected to selective process. The se- lected advantageous hallmark(s) close the cycle and lead to novel levels of Therapeutically managed can- diversity. This vicious cycle could potentially be broken if cancer cell popula- cers are under strong selec- tion is eradicated when being unable to adapt to changes after therapeutic tive pressure. The apparent intervention. limitations of chemotherapy, radiation therapy and targeted clones or even single cells [224, 225]. Indeed, therapy to eradicate cancer cells suggest that there exist real life evidence that gross genom- driver genetic lesions are not entirely responsi- ic rearrangement can compensate for a dis- ble for the therapeutic resistance and escape. ease causing mutation and prove beneficial for Indeed, initially non-clonal and passenger the patient [226]. Collectively, the high cost of mutations or epigenetic changes can provide a extreme genetic plasticity is justifiable and minor competitive advantage in the affected acceptable as it is estimated that only 0.1% of cells that become of importance under the set- species on Earth have ever adapted fast tings of specific therapy [234]. Moreover, con- enough to avoid extinction [227]. All these ventional chemotherapy and radiation therapy observations raise the hypothesis that the ideal contribute to the major hallmark themselves, scenario for a tumor to progress is the “just namely the generation and sustainable cancer right” level of cell-to-cell variation [228]. cell population diversity. Notably, chemothera- However, our proposal does not imply only py, radiotherapy and targeted therapy can also genetic mutations for generation of heteroge- cause epigenetic changes and therefore epi- neity but also epigenetic modifications as well genetic heterogeneity. At first sight our propos- as non-constant rate of accumulation of altera- al of cancer diversity as a major hallmark con- tions during cancer evolution. Furthermore, in tradicts the idea of leukemia and cancer stem our model it does not make any difference cells [235]. The counterarguments would be whether the genetic/epigenetic variation is that extensive genetic and epigenetic heteroge-

144 Int J Clin Exp Med 2019;12(1):132-157 Cancer hallmarks review neity within a bulk tumor is of limited impor- most notable success with this strategy has tance as only a very minor fraction of cancer been achieved with imatinib in chronic myeloid cells can re-establish tumor tissue and con- leukemia (CML) [254]. However, targeting the stantly sustain tumor growth [14, 236]. How- same genetic event in acute lymphoblastic leu- ever, recent experiments showed that well-dif- kemia (ALL) did not improve the long term ferentiated epithelial normal and malignant results significantly because of various resis- cells could reverse their phenotype to stem cell tance mechanisms [255-257]. Another suc- like properties [237, 238] and therefore could cessful example is the use of BRAF inhibitors in propagate the acquired genetic and epigenetic BRAF mutation positive melanoma [258, 259]. changes to the clones originating from the High resistance rate to this treatment is sup- putative cancer stem cell pool [236]. posed to be due to high tumor heterogeneity [260, 261] requiring intermittent or combined Our model suggests that to eradicate a resis- treatment strategies [262, 263]. tant cancer one has to target its core hallmark, the sustained genetic and epigenetic diversifi- Combinatorial targeted therapy is another ratio- cation, or the aspects of other hallmarks that nal approach to overcome the resistance actively contribute to it. It has already been pro- because of tumor heterogeneity [264]. It could posed that targeting the diversification and be implemented as a treatment after the iden- evolutionary processes of cancer development tification of novel drivers or as a preventive are the rational approach to the management therapy. It is believed that the so-called liquid of aggressive cancers [239, 240]. Some of the biopsies, i.e., identification of various muta- rationally proposed approaches include target- tions from cell free DNA could be translated ing clonal events, attenuation or enhancement into wide clinical use and could overcome the of , enhancing subclonal limitations of genetic testing from limited num- competition, forcing cancer populations to ber of sites of disseminated solid cancers [265, reach evolutionary constraints [228, 239]. 266]. This could help the individual tailoring of targeted therapies upfront or optimized control The obvious first question is whether modula- of the residual or relapsed tumors. Some suc- tion of genomic and epigenetic heterogeneity is cessful examples with this approach include a working strategy. The most prominent results the recent add-on of FLT3 inhibitor, midostau- that support the idea of increased mutational rin, to conventional induction therapy in AML load can be a successful strategy in cancer is [267]. Other viable approaches include combi- the introduction of PARP inhibitors in the treat- nation of EGFR and MEK inhibitors in colorectal ment of BRCA1/2 deficient cancers [241, 242]. cancer and EGFR-mutated lung cancer [268, Mutational signatures associated with AID/ 269]. APOBEC enzymes are found in a large propor- tion of human cancers [46, 243] and their Finally, in theory, the adaptive immune res- endogenous activation could potentially in- ponse has longed been considered the ideal crease the tumor mutational load to levels that approach for safe and effective cancer elimina- cannot be tolerated by the cancer cells [244, tion. Despite the evidence for active immu- 245]. Epigenetic therapy through methyltrans- noediting in numerous experimental and clini- ferase inhibitors has already reached the clinic cal settings, it has also been clear that tumors [246, 247] and seem to have a complex effect develop a number of strategies to escape on clonal evolution myeloid malignancies [248, restriction by the adaptive immune response 249]. IDH2 mutant specific inhibitor has just [270]. As mentioned above PD-1 and CTLA-4 been approved by FDA for AML treatment [250, inhibition prove to be an effective strategy of 251]. Much hope is put in the clinical develop- deblocking cytotoxic T cell specific immune ment of BET bromodomain and DOT1L inhibi- responses to cancer cells. However, the large tors [252]. Interestingly, in vitro studies suggest number of tumor driver and passenger muta- that higher mutational load can make cancer tions provide a large pool of individual cancer- cells more susceptible to common drugs [253]. specific neoantigens (the so called “muta- nome”) that could be used to design pa- Another rational approach is to target the trun- tient-tailored cancer vaccines [271]. Their com- cal mutations within the cancer population. The bination with checkpoint inhibitors might be a

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