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Heterogeneity in Tumors: An Overview

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Tumor heterogeneity-an intriguing concept

Cancer or malignant neoplasia is not any single disease but a name for a group of more than 200 related diseases all characterized by uncontrolled cellular proliferation, invasion and metastasis. It appears to be different in every single patient and continuously keeps evolving into a progressively more complex interplay of different and diverse class of tumor cells along with their ever changing environment.(1)

With the significant advancement and arrival of sophisticated model systems and technologies over the past few decades a new picture of the tumor microenvironmrent has emerged which clearly validated the presence of phenotypic, functional and genetic, heterogeneity and plasticity within and between tumours.(2) Further adding to this puzzling complexity is the skeptic heterogeneity of the tumour micro-environment, the inflammatory stimuli and immune response, mechanical stresses and other factors. These continuously varying environmental influences affect some cancer cell subpopulations which are able to survive, proliferate, spread and resist therapy. (3)Thus the term tumour heterogeneitydescribes an observation that differenttumour cellscan possess distinctmorphologicalandphenotypicprofiles, including cellular morphology, gene expression, metabolism, motility, proliferation, and metastatic potential. This may be inter-tumour heterogeneity or intra-tumour heterogeneity. In 1976 Peter Nowell for the first time proposed the current prevailing view of the process of clonal evolution involved in the formation of cancer; according to this view tumors arise with many genetic and molecular alterations succeeding multiple rounds of clonal selection (4) Clonal heterogeneity has quite a strong impact on tumor evolution. Two mechanistic pathways can be summed up. Firstly, it can be viewed as like clonal diversity provides with diverse input materials to the neoplastic cells thereby feeding them and instigating the evolution and progression of the tumor mass. Secondly,co-existence of clones which are genetically different within a tumor mass results in a well organized network of biological interactions between the clones and these interactions modulate tumor progression and responses towards generalized therapy; hence, it can be assumed that the behavior of a tumor composed of many distinct clones might be different from a tumor of monoclonal origin or the sum of the individual clones.(5) Tumor cells with different properties and variable heterogeneity can therefore be generated by cellular plasticity in response to a given microenvironment mainly via epigenetic mechanisms. So if it is evident that each cancer cell in a population is unique in its properties and different from its neighbors and some are by nature more unique than others, this should always be taken into consideration for improvement of anti cancer therapies and designing clinical trials.

Hierarchy in tumors

There is no direct or justified evidence of any specific structural hierarchy that follows in a tumor mass. It can be implicated from related findings that the innermost layer of the tumor is comprised of the typical cancer stem cells followed by the proliferative cancer cells, invasive and angiogenic cells are likely to be organized in the outer layers. Many heterogenous non-tumorigenic cell populations in the stroma surrounding tumor mass like fibroblasts, ECM, immune cells, and otherswhose function is pirated by cancer cells also contribute toward carcinogenesis and behave as members of the tumor mass increasing heterogeneity.(6) Some cancers often follow a strategy in which non-tumorigenic progeny differentiates from tumorigenic cancer stem cells thereby following a distinct hierarchy. The tumor heterogeneity can be heritable or non- heritable, usually two models have been put forward that depicts the probable cause of tumor heterogeneity, firstly the Cancer stem cell and tumor plasticity model and secondly the clonal evolution model. Both the models were supported with evidences and both appear to shed light on the concept of tumor heterogeneity. The Cancer Stem cell model states that cancers seem to be organized into a selective hierarchy maintaining subpopulations of tumorigenic cancer stem cells along with their non-tumorigenic progeny. Cancer stem cells in these cases, seems to drive the tumor progression and growth, through metastasis and therapy resistance. However, it is not evidently clear that whether the major or minor fraction of cancer cells follow this model. In cancers where a typical hierarchy of tumorigenic and non-tumorigenic cells do exists, other sources of heterogeneity, including clonal evolution heterogeneity in the micro-environment and reversible changes in the properties of cancer cell occuring independently of any specific hierar­chical organization seems to coexist. Under these prevailing circumstances it cannot be stated significantly that which functional and phenotypic differences among cancer cells arised due to which sources of heterogeneity. The concepts of cancer stem cells and clonal evolution are complementary rather than mutually exclusive as no doubt lies in the part that tumor progression is dependent on acquiring specific mutations in tumor suppressor genes and oncogenes. So this implicates that as long as the genetic and phenotypic heterogeneity do not lend any effect on the tumor stem cell population they will be considered irrelevant in terms of tumor progression as because selection only works on the those phenotypes of cancer stem cells which are heritable.

Tumor microenvironment and heterogeneity

The tumor microenvironmentcan be viewed as the cellular environment in which the tumor resides, including surrounding blood vessels, immune cells,fibroblasts, different signaling molecules juxtaposed together along with the extracellular matrix (ECM). Tumor niche can be better explained as a dynamic physiological topography in which forms of structural support , vascular supply, immune cell infiltration and growth factor accession varies drastically .(7) The coevolution of neoplastic cells together with tumor vasculature , immune cells and ECM is involved in the formation of any form of tumor. Genetic alterations solely do not determine the successful growth of tumors and eventual metastasis but it is also determined by the fitness advantage that a particular mutation confers in a given environment. Distinct environmental landscapes that persist within a given tumor select for mutations that give rise to survival and expansion of tumor mass thereby creating tumor cell heterogeneity. Although it is true that the expansion of neoplastic cells is the main trigger that initiates the creation of a tumor niche but the neighbouring non transformed cells also co-evolve during the process so that both of these cell populations can continuously and mutually participate in the process of tumorigenesis.(8) The three main participating members of the tumor microenvironment that aids in the process of tumorigenesis include Cancer Associated Fibroblasts (CAFs), tumor vasculature and immune cells. CAFs have increased proliferation signature, unique cytokine secretion and enhanced extracellular matrix production , thereby significantly promote tumorigenesis.(9) The difference in fibroblast response and behavior causes extensive remodeling of tissues mediated by increased expression of proteolytic enzymes (Membrane Metallo Proteases), deposition of ECM and pathogenic angiogenesis thereby liberating proangiogenic factors within the matrix. Heterogeneity may be attributed to the origin of the fibroblast or unique damage signals to which the fibroblasts are exposed. (10) Cellular plasticity may also exist within this cell population as both epithelial to mesenchymal and mesenchymal to epithelial transition are known to occur which further enhances the heterogeneity. The tumor vasculature networks are derived by angiogenesis and vasculogenesis. All these factors together contribute to vascular heterogeneity in and among tumors. (11)The immune cell recruitment and localization in the tumor microenvironment vary widely in and among lesions. The immune infiltrate can include different cell types, which can have both anti- and pro- tumor functions and can even vary in their activation status within the tumor. There is a constant interaction among the tumor and its surrounding microenvironment which builds a typical niche and thereby contributes to the heterogeneity in tumor cells. Tumors do influences their microenvironment by releasing signal molecules, promotingtumor angiogenesisand inducingperipheral immune tolerance. (12,13,14) The tumor microenvironment has been shown to significantly contribute to tumor heterogeneity. How tumor cells interact with their environment actually promotes tumor progression and shapes their malignant behavior. The tumor microenvironment is not homogenous as variability lies in the composition of extracellular matrix, types of infiltrating cells ,and densities of lymphatic and blood vasculature in different regions of the same tumor lesion (15,16)Thus, tumor cells within a given tumor mass experiences a wide range of microenvironmental signals, which therefore translates into diverse phenotypic manifestations.

Heterogeneity in Glioblastoma multiforme

GBM is one of the most aggressive and malignant form of brain tumor affecting adults and as the term multiforme indicates it is characterized by marked intratumoral heterogeneity. It is characterized by its robust angiogenesis and property of necrogenesis, its ability to infiltrate throughout the brain parenchyma, as well, as its intense resistance to apoptosis. Four subgroups have been identified in GBM that includes: Classical, Mesenchymal, , Neural, and Proneural, the latter further subdivided into two other classes G-CIMP and non-G-CIMP. The form of complex heterogeneity that exists in every GBM correlates with the tumor degree. The pattern of heterogeneity in most cases of GBM is linked typically to the presence of specialized sub domains within the tumor mass and a heterogeneous expression of different proteins like angiopioetin-2, MGMT, MMP-2, and integrins has also been described. (17)Comparative analysis by different studies from different regions of a single GBM tumor has demonstrated area specific chromosomal alterations and variable MGMT expression only in a subset of tumor cells. One of the major hallmarks linked with GBM heterogeneity can be substantiated to the differential expression of mutated constitutively active receptor EGFRvIII whose expression is only limited to a very small subset of cells among EGFR positive cells. EGFRvIII secretes many soluble factors such as IL-6 and LIF and thereby promotes the proliferation of cells expressing wild type EGFR. Heterogeneity in GBM was found to be either typically regional or acutely intermixed heterogeneity. lacking any specific structural hierarchy. Distribution of EGFR amplified clones and PDGFRA were observed in GBM tumor masses where PDGFRA amplified cells were found to be close to the cells of endothelium while the other EGFR amplified cells were usually found to be present in the poorly vascularized regions. An explanation to the heterogenic existence of cooperative interactions in GBM that acts to generate a mosaic pattern of cells with different alterations and phenotypic variability can be attributed to the complex interplay between different clones and subpopulations which possibly indicates that cells create a microenvironment niche that sustains the growth of other clones in the same tumor mass. A heterogeneous pattern of RTK amplification in separate regions throughout the tumors has also been viewed in GBM .The most commonly amplified RTKs include EGFR, PDGFRA and MET. A CSC fraction has been identified in these GBM tumors. These glioma-initiating cells (GBM CSCs) were suspected to be the main culprits behind tumor regrowth after therapy as they showed intense resistance to treatment than the differentiated glioma cells and have a much higher DNA repair rate. Looking at the high vascularization obtained in GBM it can be speculated that GBM CSCs might also has a similar kind of niche dependence as neural stem and the validity of this concept was found to be true. Heterogeneity in GBM is highly pronounced by the association of various factors which altogether promotes the tumorigenesis. In glioblastoma the vascular endothelial cells are capable of maintaining brain tumor cells in a stem-like state and promote their tumorigenicity. The CSCs and tumor vasculature interacts in a complex and bidirectional manner. Brain tumor CSCs promotes both angiogenesis and vasculogenesis by secreting VEGF. Inhibition of angiogenesis and depletion of blood reduces the CSC pool and, subsequently, inhibit tumor growth. The vascular microenvironment is associated with the enhanced resistance to therapeutics of GBM CSCs. Similarly glioblastoma cells induce upregulation of various survival genes in the endothelial cells, thereby protecting them from irradiation-induced apoptosis. This formidable and complex interplay can further be explained with relation to other phenomenon’s like when the notch signaling is inhibited it causes the detachment of GBM CSCs from their vascular niche and causing increased efficacy of radiotherapy on these cancer stem cells. Likewise, application of anti-angiogenic therapy to glioblastomas and complete destruction of tumor vasculature results in a much higher susceptibility of the GBM CSCs to cytotoxic agents. The regions related to to the pseudopallisading necrotic regions are essentially hypoxic, another hallmark of GBM, and this have been proposed to form a separate GBM CSC niche also, in addition to the tumor vasculature. (18) GBM CSCs are mostly located at the edges of necrotic regions. Hypoxia has shown to regulate the maintenance of GBM CSCs as in case of normal neural stem cells. These effects are mediated mainly by hypoxia-inducible factors (HIF), like HIF2 that increases the self-renewal and tumorigenic capacity of the GBM CSC pool.

Tumor markers in heterogeneity

As the tumor mass is itself heterogeneous in nature in terms of its cellular populations so it is evident that different subpopulation of cells will express different types of cellular markers characterizing their formidable phenotypic nature. As the heterogeneity can be viewed as a complex coordination of stringent biological networks originating most probably from a single source and differentiating into multiple outputs with critical interplays so it won’t be wrong to hypothesize that the properties of one cellular subpopulation residing in the tumor mass can be affected and at times modified by the foreplay of other subpopulations. Various markers for each subpopulations have been effectively studied that includes- Stemness markers like OCT4, NANOG, SOX-2, ID-1 & CD44,Proliferation markers like Ki67, PCNA & CyclineD1,EMT markers like ; Vimentin & N-Cadherin,and Angiogenesis markers like; CD31 & VEGFR2. The expression of these markers also varies according to the tumor subtype and their histologic stage. (19)Expression pattern of CD44 a cell surface glycoprotein involved in cell-cell and cell matrix adhesion along with cell migration and homing have been studied extensively in different cancer cells , a probable picture of interplay can be reviewed from the results which showed that with the overexpression of the intracellular domain of CD44 in human primary GBM cells and gliomas nanog,oct4,sox2 and id1 expression were increased.(20) In other evidences it was made clear that PCNA expression positively correlated to CD44 expression. VEGF promotes EMT transition; thereby a positive co relation lies between VEGFR2 and the EMT markers.(21)


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