Abstract
ObjectivesAdipose tissue contains a population of multipotent adipose stem cells (ASCs) that form tumor stroma and can promote tumor progression. Given the high rate of ovarian cancer metastasis to the omental adipose, we hypothesized that omental-derived ASC may contribute to ovarian cancer growth and dissemination.Materials and MethodsWe isolated ASCs from the omentum of three patients with ovarian cancer, with (O-ASC4, O-ASC5) and without (O-ASC1) omental metastasis. BM-MSCs, SQ-ASCs, O-ASCs were characterized with gene expression arrays and metabolic analysis. Stromal cells effects on ovarian cancer cells proliferation, chemoresistance and radiation resistance was evaluated using co-culture assays with luciferase-labeled human ovarian cancer cell lines. Transwell migration assays were performed with conditioned media from O-ASCs and control cell lines. SKOV3 cells were intraperitionally injected with or without O-ASC1 to track in-vivo engraftment. ResultsO-ASCs significantly promoted in vitro proliferation, migration chemotherapy and radiation response of ovarian cancer cell lines. O-ASC4 had more marked effects on migration and chemotherapy response on OVCA 429 and OVCA 433 cells than O-ASC1. Analysis of microarray data revealed that O-ASC4 and O-ASC5 have similar gene expression profiles, in contrast to O-ASC1, which was more similar to BM-MSCs and subcutaneous ASCs in hierarchical clustering. Human O-ASCs were detected in the stroma of human ovarian cancer murine xenografts but not uninvolved ovaries. ConclusionsASCs derived from the human omentum can promote ovarian cancer proliferation, migration, chemoresistance and radiation resistance in-vitro. Furthermore, clinical O-ASCs isolates demonstrate heterogenous effects on ovarian cancer in-vitro.
Highlights
Ovarian cancer is the most lethal gynecologic malignancy, resulting in 16,000 deaths per year in the United States [1]
O-ASC1 was obtained from omental adipose tissue of a patient with endometrial and ovarian adenocarcinoma without omental metastasis
O-ASC4 and O-ASC5 were isolated from grossly normal appearing omentum obtained from a patient with serous ovarian carcinoma with omental metastasis
Summary
Ovarian cancer is the most lethal gynecologic malignancy, resulting in 16,000 deaths per year in the United States [1]. The mortality and morbidity of ovarian cancer is due to a high rate of intraperitoneal dissemination and the development of chemotherapy-resistant tumors despite initially chemoresponsive disease. Intraperitoneal dissemination of ovarian cancer frequently results in the formation of metastasis in the omentum, the wellvascularized and innervated fatty tissue that lies over the bowel. We hypothesized that the omentum is a hospitable environment for the formation of ovarian cancer metastasis due to a population of tumor tropic mesenchymal stem cells in the omental adipose. We characterized a population of multi-potent adipose-derived mesenchymal stem cells from the omentum (O-ASCs) of two patients with omental disease and one without. ASCs resemble bone marrow-derived mesenchymal stem cells (BMMSCs) which have the capacity to migrate into tumors and can have been shown to promote tumor initiation, growth, vascularization, metastasis, and resistance to chemotherapy in many tumor models [3,4,5,6]. We investigated the effects of OASCs from patients with and without omental metastasis on ovarian cancer cell lines
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