Colorectal cancer is the third leading cancer worldwide and is the most common cancer in Taiwan. The average age of colorectal cancer patients has been decreased in the past few years in Taiwan. This highlights the importance and urgency to study mechanism in colon cancer. In the last decade, a subpopulation of cancer cells, termed cancer stem cells (CSCs), has been widely studied in tumorogenesis, metastastasis and relapse in colorectal cancer through selective therapy resistance and enhanced epithelial-to-mesenchymal transistion (EMT) capability. These CSCs are the key target to cure cancer; however, how the CSCs subpopulation could be maintained and preserving their stemness in the tumorous microenvironment remains unknown. Here we intend to study the microenvironmental effect of tumor-associated macrophages (TAMs) on the generation of colorectal CSCs. Our preliminary evidence demonstrates that manganese superoxide dismutase (MnSOD) is overexpressed in colorectal cancer cell lines and co-incubation with TAMs elevated the MnSOD expression even higher, leading to a significantly lower intrinsic ROS level in CRC stem-like cells. In addition, TAM-co-incubated CRC cells showed increased EMT profiles, metastatic potential and self-renewal ability. In addition, MnSOD-downregulated HCT116 cells showed less number of M2 type TAMs under co-culture system. These preliminary findings suggest that the intrinsic ROS level mediated by MnSOD may be a important target within the microenvironment where CSC generation occurs. However, the mechanisms lead tumor to evade detection and destruction by the TAMs is not clear. In this three years project, we further dissect the underlined mechanisms and its function effect on colorectal cancer cells and macrophage. Its clinical relevant are also evaluated. The following specific aims are designed to delineate the role of MnSOD in the generation of M2-type TAMs which promotes the generation of colorectal CSCs. (1) Examination of the role of MnSOD in the generation of cancer promoting microenvironment, focusing on the hypoxia effect on the expression of MnSOD and ROS in colorectal cancer cells and TAMs. (2) In vivo examination of tumorigenic effect of TAMs mediated by MnSOD expression. (3) To explore the role of MnSOD and ROS expression in colorectal cancer cell and TAMs and its clinicopathologic significance as well as preclinical evaluation of COX-2 inhibitors as tumor microenvironment modulating agents. The completion of this study will provide preclinical evidence supporting the use of modulators of tumor microenvironment as adjuvant agents for overcoming drug resistance and suppress metastasis in colorectal cancer.
|Effective start/end date||8/1/16 → 7/31/17|
- Colorectal cancer stem-like cells
- tumor microenvironment
- tumor associated macrophages
- COX-2 inhibitors