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Syndecan-1 in Stromal Fibroblasts of Breast Carcinomas
Infiltrating carcinomas characteristically elicit a reactive stromal response, and accumulating evidence indicates that tumor stroma fibroblasts reciprocally promote tumor development and growth. The cell surface heparan sulfate proteoglycan, syndecan-1 (Sdc1) is thought to function as a coreceptor for growth factor and extracellular matrix interactions, and Sdc1 expression is induced in reactive stromal cells of breast carcinomas in both mice and man. Mice with a targeted mutation in Sdc1 show reduced tumor development in response to oncogene expression, and altered responses to other pathological stimuli that are associated with the induction of stromal Sdc1. Our preliminary data demonstrate a growth-promoting loop between breast cancer cells and adjacent stromal fibroblasts that depends upon the activity of stromal cell-derived Sdc1.
We seek to test the hypothesis that Sdc1 is a key molecule mediating epithelial-stromal interactions in breast carcinoma. We propose that expression of Sdc1 by mesenchymal stromal cells promotes tumor growth by providing a mitogenic cue to epithelial carcinoma cells.
Aim 1: Determine the molecular requirements of stromal Sdc1-mediated carcinoma growth stimulation: The respective contribution of distinct molecular domains of Sdc1 will be evaluated.
Aim 2: Determine the role of stromal Sdc1 induction in breast carcinoma tumorigenesis in vivo: The contribution of stromal cell Sdc1 to carcinoma growth will be systematically evaluated in rodent models.
Aim 3: Examine stromal Sdc1 induction during breast carcinoma progression and its value as prognostic marker in infiltrating carcinomas.
In aim 1, we will examine, which domains of the Sdc1 molecule are required for carcinoma growth stimulation. Sdc1 deletion mutants and chimeric molecules will be expressed in fibroblasts and their effect on carcinoma cell growth will be examined with 2-D and 3-D co-culture models developed in our laboratory. We anticipate that fully glycanated Sdc1 expressed on the surface of fibroblasts in direct contact with carcinoma cells will be required for carcinoma growth stimulation. In aim 2, murine carcinoma cells will be inoculated into wild-type and genetically Sdc1-deficient mice to examine the role of stromal Sdc1 expression in vivo. Furthermore, fibroblast lines expressing known levels of wild-type Sdc1 or mutant Sdc1 (see aim 1) will be co-inoculated with human mammary carcinoma cells into nude mice. We anticipate that Sdc1 expression in stromal cells will promote tumorigenesis and/or growth rates. In aim 3, stromal Sdc1 expression will be examined in human breast carcinoma tissue samples. Using immunohistochemical detection of Sdc1 in tissue microarrays, we will examine the time point of stromal Sdc1 induction during carcinoma development and progression. In addition, the utility of stromal Sdc1 as predictor of time to recurrence and survival will be evaluated.
Potential Outcomes and Benefits of the Research:
This research will result in a better understanding of the molecular mechanisms underlying the communication between carcinoma cells and stromal fibroblasts. This knowledge may lead to the development of novel therapeutic approaches designed to disrupt detrimental epithelial-stromal signaling in breast cancer.
Malignant tumors including breast cancers are complex “organ systems”, which consist of multiple cell types. Through the process of invasion, genetically altered malignant tumor cells come in close contact with non-malignant connective tissue cells (fibroblasts), blood vessel cells (endothelial cells) and inflammatory cells (lymphocytes, macrophages). Collectively, these non-cancerous cells, which may constitute the main bulk of the tumor, are referred to as “tumor bed” or stroma. Cancer cells induce dramatic changes in stroma cells and recent research indicates that stroma cells in return contribute to tumor development and growth.
Molecular and genetic approaches to cancer research have greatly enhanced our understanding of the biology of breast cancer during the past decades, but most research has ignored the complex architecture of tumors and the contribution of stroma elements to tumor growth. In fact very little is known about the molecules responsible for “hijacking” the benign connective tissue cells or the nature of the growth signals fed back to the cancer cells.
Pilot experiments in our laboratory show that breast cancer cells induce the production of the molecule syndecan-1 in connective tissue fibroblasts adjacent to the cancer cells; a finding seen consistently in human breast cancer tissue samples, in mouse tumors, and in the culture dish. Interestingly, production of syndecan-1 by connective tissue cells is also found in developing breast glands of mice, re-affirming the common theme that some aspects of cancer are a caricature of normal fetal development. Syndecan-1 is not induced in connective tissue cells of prostate cancers, demonstrating the relative specificity of this event. Importantly, we find that connective tissue fibroblasts producing syndecan-1 promote the growth of breast cancer cells.
Based on these preliminary observations, we propose that syndecan-1 is a key molecule, which governs communications between cancer cells and adjacent connective tissue cells and that its presence contributes to uncontrolled growth of breast cancer.
The overall goal of our proposed research is to better understand the role of syndecan-1 in the information exchange between cancer cells and surrounding altered connective tissue cells. We will determine, which portions of the molecule are important for its function to comprehend its mechanism of action. This will be the first step towards designing strategies to inhibit these growth-promoting signals. We will also analyze human breast cancer samples using so-called “tissue chips” to determine at what stage during breast cancer development syndecan-1 appears and to test its utility as a marker for poor prognosis.
In summary, we believe that this research will lead to a much better understanding of the complex interactions between cancer cells and their microenvironment. This knowledge may lead to the development of drugs, aimed at disrupting tumor growth enhancing signaling pathways.