טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentBerger Liron
SubjectThe Role of the Tumor Microenvironment in Modulating
the Behavior of Cancer Cells
DepartmentDepartment of Medicine
Supervisors Dr. Maty Zukerman
Professor Karl Skorecki
Full Thesis textFull thesis text - English Version


Abstract

Accumulating evidence in recent years suggest that solid tumors resemble organs with abnormal structure and function. In addition to the cancer cells, tumors are composed of a variety of non-cancerous cells including mesenchymal stem cells (MSC) which provide supportive microenvironment for tumor growth, invasion and metastasis, contribute to tumor-induced neo-angiogenesis and attraction of inflammatory cells. We hypothesize that tumor development requires specific reciprocal interactions between the cancer cells and the MSC. Thus, we examined the heterogeneity of MSC derived from various tumors and their specificity in supporting tumor progression and investigated the genetic and molecular mechanisms that mediate the interactions between primary patient-derived cancer cells and their specific tumor-derived MSC (TD-MSC). For this purpose, we extracted epithelial cancer cells and stromal cells from various types of patient-derived tumors, such as breast cancer, lung squamous cell carcinoma and gastric carcinoma. The extracted stromal cells were identified as TD-MSC, as they express MSC-specific cell markers and have the capacity to differentiate in vitro into adipocytes, osteoblasts and chondrocytes. Enhanced proliferation capacity of the gastric epithelial cancer cells (GSC1) in vitro was observed in the presence of the TD-MSC derived from the same tumor (GSC-MSC)  or their conditioned medium (CM) but not in the presence of  other tumor-derived TD-MSC CM. In vivo, elevated tumorigenic capacity was observed when GSC1 cells were co-injected with their counterpart GSC-MSC and only such tumors presented a histological phenotype similar to the original patient tumor. Cytokine array analyses revealed differential expression of hepatocyte growth factor (HGF) and interleukin-6 (IL-6) between GSC-MSC and GSC1 cells. GSC-MSC mediated proliferation capacity of GSC1 cells is controlled by secretion of HGF and IL-6 from GSC-MSC via activation of HGF receptor (HGFR/c-MET) and IL-6 receptors. Interestingly, TD-MSC-derived from other tumors that were unable to support the proliferation capacity of GSC1 cells secreted no or very low levels of HGF and IL-6. Taken together, these results indicate that the niche-dependent tumorigenic capacity of GSC1 cells is mediated by their counterpart TD-MSC via HGF and IL-6 secretion. Accordingly, our findings demonstrate that the interactions between the tumor cancer cells and MSC within a single tumor are niche-specific and play a crucial role in tumor development and progression. Understanding the mechanisms underlying such tumor specific cancer cell-stromal cells interaction should lead to more precise therapeutic approaches.