Tumor-associated macrophages remodeling EMT and predicting survival in colorectal carcinoma

Abstract

The immune contexture, a composition of the tumor microenvironment, plays multiple important roles in cancer stem cell (CSC) and epithelial-mesenchymal transition (EMT), and hence critically influences tumor initiation, progression and patient outcome. Tumor-associated macrophages (TAMs) are abundant in immune contexture, however their roles in CSC, EMT and prognosis of colorectal cancer (CRC) have not been elucidated. In 419 colorectal carcinomas, immune cell types (CD68 macrophages, CD3, CD4 or CD8 T lymphocytes, CD20 B lymphocytes), EMT markers (E-cadherin and Snail) as well as the stem cell marker (CD44v6) were detected in tumor center (TC) and tumor invasive front (TF) respectively by immunohistochemistry. Tumor buds, that represent EMT phenotype, were also counted. It was found CD68 macrophages were the most infiltrating immune cells in CRC. By correlation analysis, more CD68 macrophages were associated with more CD44v6 expression (p < 0.001), lower Snail expression (p = 0.08) and fewer tumor buds (p < 0.001). More CD68 macrophages were significantly related to more CD3 T lymphocytes (p = 0.002), CD8 T lymphocytes (p < 0.001) and CD20 B lymphocytes counts (p = 0.004). Strong CD68 macrophages infiltration also predicted long term overall survival. CRC patients with more tumor buds had worse survival. However, strong CD68 macrophages infiltration could reverse the unfavorable results since patients with more tumor buds but increasing CD68 macrophages infiltration had the favorable outcome, similar to lower tumor buds groups. This study provided direct morphological evidence that tumor-associated macrophages in the invasive front play critical roles in fighting with the unfavorable results of tumor buds, thus resulting favorable outcomes for CRC patients.

Tumor cell‐derived TGF‐β at tumor center independently predicts recurrence and poor survival in oral squamous cell carcinoma

“…For instance, it has been reported that tumorassociated macrophages could be recruited to ITF and induce the immune response, which play critical protective roles against unfavorable outcomes of tumor buds. 23 These results indicate that it is at TC regions, not ITF regions, that TGF-β mainly exerts tumor promotor, resulting in unfavorable clinical outcomes. To date, this is the first report on regional heterogenous expression of TGF-β combined cell types, including tumor cells, FLCs, and TILs in OSCC.…”

“…Thirdly, some cell types at ITF regions function as anti‐tumor role by regulating the immune response. For instance, it has been reported that tumor‐associated macrophages could be recruited to ITF and induce the immune response, which play critical protective roles against unfavorable outcomes of tumor buds . These results indicate that it is at TC regions, not ITF regions, that TGF‐β mainly exerts tumor promotor, resulting in unfavorable clinical outcomes.…”

Study of Tumor Microenvironment and Host Response in Colorectal Cancer: Immunohistochemical and Clinicopathological Approach

“…Similar results were reported by Waniczek et al [31] and Cui et al [32] who concluded that increase intensity of macrophage is associated with unfavorable prognosis. Contradictory results were reported by Forssell et al [33] and Li et al [34] who found a significant positive correlation between intense infiltrations of CD68 and improved prognosis of CRC.…”

Identification of key genes related to dexamethasone-resistance in acute lymphoblastic leukemia

“…The high levels of the adhesion molecule CD44 on leukemic cells were essential to generate leukemia [42] . CD44 was considered as cancer stem cell-like marker [43] . However, the value upon drug resistance of CD44 in neoplasms remains controversial [44] .…”