Tumor-Associated Macrophages (TAMs) Form an Interconnected Cellular Supportive Network in Anaplastic Thyroid Carcinoma

Abstract

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.

The immune network in thyroid cancer

“…66 TAMs represent more than 50% of immune cells in ATCs forming a "microglia-like" in close contact with cancer cells. 69 In diffuse sclerosing variant of PTC, M2-like macrophages can be found in lymphatic emboli and correlated with tumor cell lymphatic invasion. 70 In a murine model of transgenic BRAF (V600E) -induced thyroid carcinogenesis, tumors displayed a high TAM infiltration due to the increased expression of CSF-1 and CCL2 by tumor cells.…”

Thyroid cancer metabolism: A review

“…For instance, high T-regulatory cell density correlates with thyroid cancer aggressiveness, and an increased number of immunoregulatory natural killer cells has been demonstrated in PTC compared to normal tissues [39,40]. Furthermore, is has been shown that the degree of lymphocyte and immature dendritic cell infiltration correlated with better prognosis in PTC [41,42], whereas increased macrophage density in poorly differentiated thyroid carcinoma correlated with invasive features and worsened prognosis [43]. Jung et al found that tumor-associated macrophage density correlated with more aggressive subtypes, like anaplastic thyroid carcinoma [44].…”

Vasoactive intestinal peptide represses activation of tumor-associated macrophages in gastric cancer via regulation of TNFα, IL-6, IL-12 and iNOS

“…Moreover, the treatment with VIP inhibits the expression of TNFα, IL-6, IL-12 and iNOS in TAM, which results in deactivation of TAM. For cancer cells, TAM acts as mediators for interacting growth factors, cytokines and chemokines and change the tumor microenvironment to stimulate tumor progression (25)(26)(27). We demonstrated that the VIP inhibited gastric cancer via TAM both in cultured cells and in the nude mouse model.…”