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Tumor-associated macrophages (TAMs) depend on Shp2 for their anti-tumor roles in colorectal cancer.

ABSTRACT: Tumor associated macrophages (TAMs) in tumor microenvironment can interact with tumor cells and are related to tumor progression. However, the mechanisms that drive the anti-tumor functions of TAMs are not fully understood. The Src homology 2 domain-containing tyrosine phosphatase 2 (Shp2) has been reported to have tumor-suppressing roles in colorectal cancer (CRC). However, a role for Shp2 on TAMs in CRC has not been studied. Here we report that in CRC, Shp2 expression on TAMs is negatively associated with liver metastasis. TAMs require Shp2 for their anti-tumor functions in a cell-cell co-culture system and a mouse model of CRC. Mechanistically, absence of Shp2 on TAMs induces their polarization toward M2 phenotype through the activation of p-STAT3 and inhibition of p-NF-κB p65. The findings of our study imply that Shp2 is a key factor in the tumor microenvironment to facilitate the TAMs' tumor-suppressing functions in colorectal cancer.

SUBMITTER: Wang S

PROVIDER: S-EPMC6780667 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundA relationship between the increased density of tumor-associated macrophages (TAMs) and decreased survival was recently reported in thyroid cancer patients. Among these tumors, anaplastic thyroid cancer (ATC) is one of the most aggressive solid tumors in humans. TAMs (type M2) have been recognized as promoting tumor growth. The purpose of our study was to analyze with immunohistochemistry the presence of TAMs in a series of 27 ATC.Methodology/principal findingsSeveral macrophages markers such as NADPH oxidase complex NOX2-p22phox, CD163 and CD 68 were used. Immunostainings showed that TAMs represent more than 50% of nucleated cells in all ATCs. Moreover, these markers allowed the identification of elongated thin ramified cytoplasmic extensions, bestowing a "microglia-like" appearance on these cells which we termed "Ramified TAMs" (RTAMs). In contrast, cancer cells were totally negative. Cellular stroma was highly simplified since apart from cancer cells and blood vessels, RTAMs were the only other cellular component. RTAMs were evenly distributed and intermingled with cancer cells, and were in direct contact with other RTAMs via their ramifications. Moreover, RTAMs displayed strong immunostaining for connexin Cx43. Long chains of interconnected RTAMs arose from perivascular clusters and were dispersed within the tumor parenchyma. When expressed, the glucose transporter Glut1 was found in RTAMs and blood vessels, but rarely in cancer cells.ConclusionATCs display a very dense network of interconnected RTAMs in direct contact with intermingled cancer cells. To our knowledge this is the first time that such a network is described in a malignant tumor. This network was found in all our studied cases and appeared specific to ATC, since it was not found in differentiated thyroid cancers specimens. Taken together, these results suggest that RTAMs network is directly related to the aggressiveness of the disease via metabolic and trophic functions which remain to be determined.

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Tumor-associated macrophages (TAMs) depend on Shp2 for their anti-tumor roles in colorectal cancer.

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