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  • CIC mediated chemoresistance is driven by several factors

    2019-07-02

    CIC-mediated chemoresistance is driven by several factors. In our quest to learn about these, we examined the crucial mediators identified earlier in the regulation of CSC survival and chemoresistance, such as BCL2, cleaved Caspase-3, COX-2, and macrophages. Interestingly, we observed a significantly greater amount of BCL2 protein in DMSO-treated tumors, which corresponds well with increased stem cell marker expression. BCL2 protein is an integral component of the cell survival mechanism that determines cellular fate by maintaining the protein phosphatase inhibitor balance between cell apoptosis and survival. Many signaling components, either upstream or downstream of BCL2, have been identified in regulating CSC survival and chemoresistance. The BCL2 protein family is implicated in the chemoresistance mechanism of CICs against oxaliplatin and 5-FU [34]. In CICs, BCL2 confers chemoresistance via activating the AKT signaling pathway [35]. In this study, Mo lowered BCL2 expression in tumors, which correlates well with decreased numbers of CSCs in Mo-treated tumors. Furthermore, the cleaved Caspase-3 levels were also increased upon Mo treatment, which serves as a marker of apoptosis. Mo likely activates apoptosis via reducing BCL2 levels in tumor cells, including CSCs, and this leads to shrinking tumors at an increased rate. The shrinkage of the tumors is also affected by our finding that Mo triggers a reduced proliferation in both HT-29 and SW-480 colon cancer cells. Interaction between CSCs and stromal protein phosphatase inhibitor is considered as one possible mechanism whereby CSCs can promote tumor growth. A phenotypically distinct population of macrophages, known as tumor-associated macrophages (TAMs), is found to be present in the proximity of CSCs [36]. In addition, we have recently shown that TAM-M2 macrophages induces colon cancer cell invasion via MMP-9 expression [37]. Furthermore, CSCs secrete many factors such as CCL2, CCL5, CCL7 and VEGF-A, which apparently facilitate macrophage recruitment [38]. In agreement with this, we found that vehicle-treated tumors with high ALDH1 expression were greatly infiltrated by M2 macrophages, identified with high Arg1 and CD206 expression. However, inhibition of CysLT1R by Mo tends to lower the total macrophage infiltration within HT-29-derived tumors. These data imply that CysLT1R could play an important role in the recruitment of macrophages to the site of the growing tumor. The interplay between CSCs and TAMs stimulates specific growth factor production, which promotes angiogenesis and immune tolerance. These events likely support CSC-induced tumor growth by triggering STAT3 and hedgehog signaling [39]. Mo, therefore, might have a role whereby these interactions can be prevented yielding reduced tumor growth. Further, we detected reduced COX-2 levels and elevated 15-PGDH levels in HT-29 cell tumors of mice treated with Mo. COX-2 is a crucial element in the prostaglandin synthesis pathway [40]. It imparts proliferative properties to tumor cells. Our results suggest that Mo reduces the proliferative activity of tumor cells, probably by decreasing COX-2 levels and activating the prostaglandin-degrading enzyme 15-PGDH [25,41] which may also prevent drug resistance. It is noteworthy, however, that SW-480 cell-derived tumors displayed moderate COX-2 but strong 15-PGDH staining. Although SW-480 cells were reported to express very low levels of COX-2 [42], considering that tumors were extensively infiltrated by host immune cells, which can express COX-2, it is likely we detected COX-2 protein within tumors.
    Conclusion We observed that colonospheres, as well as tumor growth in mice, correlates significantly with the amount of CSCs. This yields higher survival probability conferred by high ALDH1, BCL2 levels, and M2 macrophage infiltration of tumors. Inhibition of CysLT1R signaling seems to be beneficial in reducing CSC number, lowering survivability and decreasing tumor growth, in summary see Fig. 8. CysLT1R signaling seemingly relates to ALDH1, DCLK1, BCL2, COX-2 and macrophage levels. Thus, it can be inferred that variation in CSC numbers within tumors could affect their growth. Hence, targeting CSCs could prove instrumental in addressing chemotherapeutic failures and the associated tumor relapses in patients afflicted with colon cancer.