Review Article All Cancer Hallmarks Lead to Diversity

Int J Clin Exp Med 2019;12(1):132-157 www.ijcem.com /ISSN:1940-5901/IJCEM0072581 Review Article All cancer 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 biology. 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 cancer cell 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 hallmarks 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 mutations 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 hallmark. 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 mutation 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 cancers 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

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