Niche-Dependent Gene Expression Profile of Intratumoral Heterogeneous Ovarian Cancer Stem Cell Populations

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.

Molecular changes in endometriosis-associated ovarian clear cell carcinoma

“…Hence, the expression of these extensively large lineage-specifying gene sets in endometriosis but silenced in OCCC suggests an epigenetic reprogramming mechanism that transforms the differentiated endometriotic cells to a pluripotent state in OCCC. To this end, many studies have suggested that OCCC is particularly enriched with subpopulations of cancer stem cells [38, 39]. Since reprogramming to a pluripotent state involves increased activity of defined transcription factors, our GSEA analysis using Motif gene set collection revealed enrichment of Elk1 and YY1 target genes in OCCC (Table S9).…”

Reciprocal Reprogramming of Cancer Cells and Associated Mesenchymal Stem Cells in Gastric Cancer

“…This complex intratumoral heterogeneity contributes to the "nefarious ingenuity" of human cancers and challenges their eradication. Accumulating evidence shows that both the "cancer stem cells" (CSCs) and the "clonal evolution" models, can explain the intratumoral heterogeneity, as CSCs undergo clonal evolution [15][16][17][18][19][20][21][22]. The continuous accumulation of mutations generates heterogeneity of cells within a solid tumor and its metastases, causing certain subsets of tumor cells become more aggressive during tumor progression.…”

“…This facilitates invasion and metastasis of cancer cells, enables non-CSCs to convert into CSCs, and may influence the TME by converting cancer cells into tumor supportive stroma [23][24][25][26]. The complexity and plasticity of solid tumors is enabled by a TME that provides a compatible network of interactions between the heterogeneous cancer cells and non-neoplastic tumor-supporting cells [19,[27][28][29]. Therefore, attempts to eradicate a single stable self-renewing subpopulation within any given tumor are often futile.…”

Theranostic barcoded nanoparticles for personalized cancer medicine

“…To prescreen multiple drugs for their anticancer activity, in vitro and in vivo assays were developed78. These tests are based on tumour tissue that is biopsied from a patient and then either grown in a dish ( in vitro ) or implanted into immune-deficient mice ( in vivo )7.…”

“…These tests are based on tumour tissue that is biopsied from a patient and then either grown in a dish ( in vitro ) or implanted into immune-deficient mice ( in vivo )7. Subsequently, the cells, or the mice, are treated with various drugs to predict the most efficient treatment.…”