| Summary: | 碩士 === 國防醫學院 === 病理及寄生蟲學研究所 === 104 === Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. The prognosis of CRC is usually poor because of its propensity for extensive invasion, local recurrence and frequent regional lymph node metastasis. Researches have shown Carcinoma-associated fibroblasts (CAFs), a major type of tumor-surrounding stromal cell, generate mediators, such as Stromal Cell-Derived factor 1 (SDF-1), through which they interact with tumors and contribute to the progression and increase of stemness of cancer. The orchestration between CAFs and CRC cells is complex. Despite recent studies demonstrating the paracrine effect of stromal cells in the tumor microenvironment on initiation and progression of colorectal cancer cells, the major mediator related to CAFs and its underlying mechanism still remain unknown.
Based on our present study, we found that the expression of SDF-1 and its receptor C-X-C chemo receptor type 4 (CXCR4) are stronger when co-cultured with CAFs than with NFs. In addition, ELISA assay also validates the presence of SDF-1 that is responsible for the crosstalk between fibroblasts and CRC cells via the paracrine effect. Furthermore, the mediator SDF-1 not only triggers epithelial-mesenchymal-transition (EMT), showing upregulation of EMT markers in RNA and proteins levels, but also improves the capabilities of migration and invasion. CRC cells treated with recombinant SDF-1, mimics the CAFs-CRC paracrine route, increased capabilities of sphere formation in ten days. To simulate SDF-1-induced autocrine signaling, we established stable clones of SDF-1-overexpressing CRC cells. Stable clone CRC cells exhibited the epithelial-mesenchymal-transition, increased mobility and upregulation of drug-resistant genes. In vivo study reconfirmed the functional role of SDF-1 in tumor initiation. Immunohistochemistry of tumor dissected from mouse confirmed that autocrined-SDF-1 enhances CSCs properties through different pathways than paracrine. Besides the paracrine signaling, we clearly verified that CAFs-induced SDF-1 reciprocally triggered cancer cells to produce SDF-1 in an autocrine manner, which resulted in the binding to CXCR4 and cancer progression. Further studies include evaluations of the mechanism of autocrine signaling. Meanwhile, validates in clinical patients.
Our results verify that CAFs promote cancer invasiveness via paracrine and autocrine effects on microenvironmental SDF-1 signaling, and suggest that SDF-1 is a potentially biomarker which contributes to the expression of CSC properties, and may provide as a therapeutic option for improving prognosis in patients with CRC.
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