Abstract
Intratumoral heterogeneity challenges existing paradigms for anti-cancer therapy. We have previously demonstrated that the human embryonic stem cells (hESC)-derived cellular microenvironment in immunocompromised mice, enables functional distinction of heterogeneous tumor cells, including cells which do not grow into a tumor in a conventional direct tumor xenograft platform. We have identified and characterized six cancer cell subpopulations each clonally expanded from a single cell, derived from human ovarian clear cell carcinoma of a single tumor, to demonstrate striking intratumoral phenotypic heterogeneity that is dynamically dependent on the tumor growth microenvironment. These cancer cell subpopulations, characterized as cancer stem cell subpopulations, faithfully recapitulate the full spectrum of histological phenotypic heterogeneity known for human ovarian clear cell carcinoma. Each of the six subpopulations displays a different level of morphologic and tumorigenic differentiation wherein growth in the hESC-derived microenvironment favors growth of CD44+/aldehyde dehydrogenase positive pockets of self-renewing cells that sustain tumor growth through a process of tumorigenic differentiation into CD44-/aldehyde dehydrogenase negative derivatives. Strikingly, these derivative cells display microenvironment-dependent plasticity with the capacity to restore self-renewal markers and CD44 expression. In the current study, we delineate the distinct gene expression and epigenetic profiles of two such subpopulations, representing extremes of phenotypic heterogeneity in terms of niche-dependent self-renewal and tumorigenic differentiation. By combining Gene Set Enrichment, Gene Ontology and Pathway-focused array analyses with methylation status, we propose a suite of robust differences in tumor self-renewal and differentiation pathways that underlie the striking intratumoral phenotypic heterogeneity which characterize this and other solid tumor malignancies.
Highlights
It is widely appreciated that a single tumor is comprised of heterogeneous cell populations, each of which displays a diverse cellular morphology, phenotypic expression, tumor initiation capacities and inherent or acquired resistance to anticancer drugs
We have recently reported the observation that consistent heterogeneity in tumorigenic properties among six different Ovarian clear cell carcinoma (OCCC)-derived cancer cell subpopulations (CCSPs) was most strikingly reflected in their niche-dependent in vivo tumorigenic capacities and tumor cellular phenotypes [36], and that the human embryonic stem cells (hESC)–derived niche further supports self-renewing cancer stem cells' (CSC) and exposes their full repertoire of tumorigenic phenotypes [5]
In order to shed light on the tumor microenvironment contribution to this heterogeneity, we focused on gene expression microarray analyses to characterize the gene expression profiles of two distinct cancer cell subpopulations, CCSP C12 and C13 which grow successfully in both the xenotransplantation and the hESC-based teratoma models, and which exhibit the extremes of tumorigenic phenotypic attributes and niche-dependent selfrenewal capacity [5,36]
Summary
It is widely appreciated that a single tumor is comprised of heterogeneous cell populations, each of which displays a diverse cellular morphology, phenotypic expression, tumor initiation capacities and inherent or acquired resistance to anticancer drugs. The aggressiveness and ingenuity of human cancers emanate mainly from such complex intratumoral heterogeneity, which in turn has been attributed to genetic and epigenetic changes coupled with adaptive responses to the tumor microenvironment. The complexity and plasticity of solid tumors emanates from the requirement of a supportive microenvironment that provides a compatible network of interactions between the heterogeneous cancer cells and various tumor-supporting cells [12,13,14,15,16]. Recruitment of tumor supporting multipotent mesenchymal stem cells coupled with extensive remodeling of adjacent tissues is an essential process for providing a microenvironment which supports cancer cell proliferation, migration and invasion [17,18]. The specific processes which have been most extensively studied include neoangiogenesis [19], attraction of inflammatory cells [20] and cancer associated fibroblasts [21,22,23] which together with the extracellular matrix (ECM) create the complexity of the tumor mass [24]
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