Molecular and Cellular Endocrinology 175 (2001) 29 – 39 Stromal-epithelial interactions in the progression of ovarian cancer: influence and source of tumor stromal cells Jeff A. Parrott a,1 , Eric Nilsson a , Rachel Mosher a , Gregg Magrane b , Donna Albertson b , Daniel Pinkel b , Joe W. Gray b , Michael K. Skinner a, * a Center for Reproductie Biology, School of Molecular Biosciences, Washington State Uniersity, Pullman, WA 99164 -4231, USA b Cancer Center, Uniersity of California, San Francisco, San Francisco, CA 94143 -0808, USA Received 4 September 2000; accepted 25 January 2001 Abstract Stromal cells are essential for the progression of many cancers including ovarian tumors. Stromal cell-epithelial cell interactions are important for tumor development, growth, angiogenesis, and metastasis. In the current study, the effects of normal ovarian bovine stromal cells on ovarian tumor progression was investigated. The hypothesis tested is that ovarian stromal cells will alter the onset and progression of ovarian tumors. Conditioned medium from normal bovine ovarian surface stromal cells was found to stimulate the growth of normal ovarian surface epithelium and had no effect on the growth of human tumor cell lines SKOV3 and OCC1. Human ovarian cancer cell lines, SKOV3 and OCC1, were injected subcutaneously into nude mice to examine tumor progression. Tumor growth in the nude mice was dramatically reduced when normal ovarian surface stromal cells were co-injected with SKOV3 or OCC1 cells. Similar results were obtained with normal bovine or human ovarian stromal cells. In contrast, irrelevant testicular stromal cells and epithelial cells had no effect on tumor growth in the nude mouse. Histological examination of these tumors revealed a characteristic stromal cell component adjacent to epithelial cell colonies. Sections of these tumors were hybridized with species specific genomic probes using fluorescence in situ hybridization to identify cell populations. Epithelial cells were shown to be of human origin (i.e. SKOV3 or OCC1), but stromal cells were found to be primarily murine in origin (i.e. host tissue). No detectable bovine cells were observed in the tumors after one week post-injection. Results suggest that stromal cells are an essential component of ovarian tumors. Interestingly, normal ovarian stromal cells had the ability to inhibit tumor growth, but were not able to survive long-term incubation at the tumor site. The developing tumor appears to recruit host (i.e. murine) stromal cells to invade the tumor and support its growth. In summary, normal ovarian stromal cells can inhibit ovarian tumor progression and the developing tumors recruit adjacent host stroma to become ‘‘tumor stroma’’. The tumor stroma likely develop an altered phenotype that cooperates with the tumorigenic epithelial cells to help promote the progression of ovarian cancer. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Mesenchymal-epithelial; Ovary; Ovarian cancer; Ovarian surface epithelium; Stroma; Tumor progression www.elsevier.com/locate/mce 1. Introduction Ovarian cancer ranks fifth as a cause of cancer related death among women. It is estimated that there will be 20 000 deaths per year from ovarian cancer in the United States (ACS, 1998). Greater that 95% of ovarian cancers originate in the epithelial cells on the surface of the ovary (Weiss et al., 1977; Piver et al., 1991) referred to as the ovarian surface epithelium (OSE). The OSE is a modified mesothelium covering the surface of the ovary. It is a simple epithelium separated from underlying ovarian stromal tissue by a basal lamina of collagenous connective tissue (Nicosia and Nicosia, 1988). Both the OSE and stroma con- tribute to the extracellular matrix (ECM) that separates the two cell types (Auersperg et al., 1991). The cellular associations between OSE and stroma have been shown to influence the intermediate filaments in the OSE that may be compared with the early stages of neoplastic * Corresponding author. Tel.: +1-509-335-1524; fax: +1-509-335- 2176. E-mail address: skinner@mail.wsu.edu (M.K. Skinner). 1 Present Address: Atairgin Technologies, Inc., 101 Theory, Suite 150, Irvine, CA 92612, USA. 0303-7207/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII:S0303-7207(01)00436-1