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Tumor-Associated Macrophages (TAMs): A Critical Activator In Ovarian Cancer Metastasis.

ABSTRACT: Tumor-associated macrophages (TAMs) that appear in every stage of cancer progression are usually tumor-promoting cells and are present abundantly in the tumor-associated microenvironment. In ovarian cancer, the overall and intratumoral M1/M2 ratio is a relatively efficient TAM parameter for predicting the prognosis of patients, especially for serous tissue type cancer. TAMs exhibit immunological checkpoint modulators, such as the B7 family and programmed death-ligand 1 (PD-L1), and play a key role in the development, metastasis and invasion of ovarian cancer, but the underlying mechanism is barely understood. Ovarian cancer is a severe gynecological malignancy with high mortality. Ovarian cancer-associated death can primarily be attributed to cancer metastasis. The majority of patients are diagnosed with wide dissemination in the peritoneum and omentum, limiting the effectiveness of surgery and chemotherapy. In addition, unlike other well-documented cancers, metastasis through vasculature is not a usual dissemination pathway in ovarian cancer. This review sheds light on TAMs and the main process and mechanism of ovarian cancer metastasis.

SUBMITTER: Yin M

PROVIDER: S-EPMC6814357 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Tumor-Associated Macrophages (TAMs): A Critical Activator In Ovarian Cancer Metastasis.

Yin Meichen M Shen Jiayu J Yu Shuqian S Fei Jing J Zhu Xiaoqing X Zhao Jiayao J Zhai Lingyun L Sadhukhan Annapurna A Zhou Jianwei J

OncoTargets and therapy 20191021

Tumor-associated macrophages (TAMs) that appear in every stage of cancer progression are usually tumor-promoting cells and are present abundantly in the tumor-associated microenvironment. In ovarian cancer, the overall and intratumoral M1/M2 ratio is a relatively efficient TAM parameter for predicting the prognosis of patients, especially for serous tissue type cancer. TAMs exhibit immunological checkpoint modulators, such as the B7 family and programmed death-ligand 1 (PD-L1), and play a key ro ...[more]

PMID: 31695427

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Project description:In the tumor micro-environment, tumor associated macrophages (TAMs) represent a predominant component of the total tumor mass, and TAMs play a complex and diverse role in cancer pathogenesis with potential for either tumor suppressive, or tumor promoting biology. Thus, understanding macrophage localization and function are essential for cancer diagnosis and treatment. Typically, tissue biopsy is used to evaluate the density and polarization of TAMs, but provides a limited "snapshot" in time of a dynamic and potentially heterogeneous tumor immune microenvironment. Imaging has the potential for three-dimensional mapping; however, there is a paucity of macrophage-targeted contrast agents to specifically detect TAM subtypes. We have previously found that sulfated-dextran coated iron oxide nanoparticles (SDIO) can target macrophage scavenger receptor A (SR-A, also known as CD204). Since CD204 (SR-A) is considered a biomarker for the M2 macrophage polarization, these SDIO might provide M2-specific imaging probes for MRI. In this work, we investigate whether SDIO can label M2-polarized cells in vitro. We evaluate the effect of degree of sulfation on uptake by primary cultured bone marrow derived macrophages (BMDM) and found that a higher degree of sulfation led to higher uptake, but there were no differences across the subtypes. Further analysis of the BMDM showed similar SR-A expression across stimulation conditions, suggesting that this classic model for macrophage subtypes may not be ideal for definitive M2 subtype marker expression, especially SR-A. We further examine the localization of SDIO in TAMs in vivo, in the mammary fat pad mouse model of breast cancer. We demonstrate that uptake by TAMs expressing SR-A scales with degree of sulfation, consistent with the in vitro studies. The TAMs demonstrate M2-like function and secrete Arg-1 but not iNOS. Uptake by these M2-like TAMs is validated by immunohistochemistry. SDIO show promise as a valuable addition to the toolkit of imaging probes targeted to different biomarkers for TAMs.

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.

Dataset Information

Tumor-Associated Macrophages (TAMs): A Critical Activator In Ovarian Cancer Metastasis.

Publications

Tumor-Associated Macrophages (TAMs): A Critical Activator In Ovarian Cancer Metastasis.

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