Abstract

BackgroundOvarian cancer is a complicated malady associated with cancer stem cells (CSCs) contributing to 238,700 estimated new cases and 151,900 deaths per year, worldwide. CSCs comprise a tiny fraction of tumor-bulk responsible for cancer recurrence and eventual mortality. CSCs or tumor initiating cells are responsible for self-renewal, differentiation and proliferative potential, tumor initiation capability, its progression, drug resistance and metastatic spread. Although several biomarkers are implicated in these processes, their distribution within the ovary and association with single cell type has neither been established nor demonstrated across ovarian tumor developmental stages. Therefore, precise identification, thorough characterization and effective targeted destruction of dormant and highly proliferating potent CSC populations is an immediate need.ResultsIn view of this, distribution of various CSC (ALDH1/2, C-KIT, CD133, CD24 and CD44) and cell proliferation (KI67) specific markers in the ovarian surface epithelium (OSE) and cortex regions in normal ovary, and benign, borderline and high grade metastatic ovarian tumors by immuno-histochemistry and confocal microscopy was studied. We further confirmed their expression by RT-PCR analysis. Co-expression analysis of stem cell (OCT4, SSEA4) and CSC (ALDH1/2, CD44 and LGR5) markers with proliferation marker (KI67) in HG tumors revealed dual positive proliferating stem and CSCs, few non-proliferating stem/CSC (SSEA4+/KI67− and ALDH1/2+/KI67−) and only KI67+ cells in cortex, signifying dynamic populations and interesting cellular hierarchy in cortex region. Smaller spherical (≤ 5 μm) and larger spindle/elliptical shaped (~ 10 μm) cell populations with high nucleo-cytoplasmic ratio were detected across all samples (including normal ovaries) but with variable distribution and characteristic stage-wise marker expression across different tumor stages.ConclusionsDiverse stem and CSC populations expressing characteristic markers revealing distinct phenotypes (spherical ≤5 μm and spindle/elliptical ~ 10 μm) were distributed within different tumor stages studied signifying dynamic and probable functional hierarchy within these cell types. Involvement of extra-ovarian sites of origin of stem and CSCs requires rigorous evaluation. Quantitative analysis of potent CSC populations, their mechanisms and pathways for self-renewal, chemo-resistance, metastatic spread etc. with respect to various markers studied, will provide better insights and targets for developing effective therapeutics to prevent metastasis and eventually help improve patient mortality.

Highlights

  • Ovarian cancer is a complicated malady associated with cancer stem cells (CSCs) contributing to 238,700 estimated new cases and 151,900 deaths per year, worldwide

  • In our present study, we focused on understanding the distribution of various CSC-specific markers in normal ovary and various stages of ovarian tumorigenesis (BN, BL and high grade (HG)), and characterization of CSCs in HG metastatic ovarian cancer tissues (Figs. 1A, B, 2A, B and 3A, B, Additional file 1: Figure S1 and Additional file 2: Figure S2) and their co-localization with cell proliferation marker [KI67] (Figs. 4, 5, 6, 7 and 8, Additional file 3: Figure S3, Tables 3 and 4)

  • Based on co-expression studies we found existence of dual positive proliferating stem cells and CSCs, few dormant stem/ CSCs (SSEA4+/KI67− and ALDH1/2+/KI67−) and only KI67+ cells signifying dynamic populations and interesting cellular hierarchy in the cortex region

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Summary

Introduction

Ovarian cancer is a complicated malady associated with cancer stem cells (CSCs) contributing to 238,700 estimated new cases and 151,900 deaths per year, worldwide. It is established that tumor is comprised of heterogeneous cancer cell populations at various stages of differentiation and a tiny fraction of CSC populations This heterogeneity leads to a serious bottleneck for effectively targeting these highly dynamic, transitioning populations of CSCs. Existence of diverse CSC populations with stem cell like characteristics at a given point and a cross talk between tissue microenvironment, various genetic and non-genetic (epigenetic) factors and dysregulation between these mechanisms impose drug resistance, tumor recurrence and metastasis [6, 8]. Purpose of present study is to (i) identify stem cells residing in normal ovary versus ovarian tumors including benign (BN), borderline (BL) and high grade (HG) (malignant stage) and (ii) delineate if highly proliferating cells in HG ovarian tumor are differentiated cancer cells and/or (cancer) stem cell populations per se by using a panel of markers

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