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Molecular pathways: VCAM-1 as a potential therapeutic target in metastasis.

ABSTRACT: Interactions between disseminated tumor cells (DTC) and stromal cells in the microenvironment are critical for tumor colonization of distal organs. Recent studies have shown that vascular cell adhesion molecule-1 (VCAM-1) is aberrantly expressed in breast cancer cells and mediates prometastatic tumor-stromal interactions. Moreover, the usefulness of VCAM-1 to DTCs in 2 different organs--lung and bone--is based on distinct mechanisms. In the lungs, VCAM-1 on the surface of cancer cells binds to its counterreceptor, the ?4?1 integrin (also known as very-late antigen, VLA-4), on metastasis-associated macrophages, triggering VCAM-1-mediated activation of the phosphoinositide 3-kinase growth and survival pathway in the cancer cells. In the bone marrow, cancer cell VCAM-1 attracts and tethers ?4 integrin-expressing osteoclast progenitors to facilitate their maturation into multinucleated osteoclasts that mediate osteolytic metastasis. These findings highlight the importance of direct interactions between DTCs and stromal cells during tumor dissemination and draw attention to the possibility of targeting the ?4 integrin-VCAM-1 interactions in metastatic breast cancer. Anti-?4 integrin inhibitors have been developed to treat various diseases driven by massive leukocyte infiltrates and have gained U.S. Food and Drug Administration approval or are undergoing clinical trials. Testing these drugs against tumor-stromal leukocyte interactions may provide a new strategy to suppress lung and bone relapse of breast cancer.

SUBMITTER: Chen Q

PROVIDER: S-EPMC3473104 | biostudies-other | 2012 Oct

REPOSITORIES: biostudies-other

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Molecular pathways: VCAM-1 as a potential therapeutic target in metastasis.

Chen Qing Q Massagué Joan J

Clinical cancer research : an official journal of the American Association for Cancer Research 20120809 20

Interactions between disseminated tumor cells (DTC) and stromal cells in the microenvironment are critical for tumor colonization of distal organs. Recent studies have shown that vascular cell adhesion molecule-1 (VCAM-1) is aberrantly expressed in breast cancer cells and mediates prometastatic tumor-stromal interactions. Moreover, the usefulness of VCAM-1 to DTCs in 2 different organs--lung and bone--is based on distinct mechanisms. In the lungs, VCAM-1 on the surface of cancer cells binds to i ...[more]

PMID: 22879387

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Project description:Brain metastasis is a common complication of cancer patients and is associated with poor survival. Histological data from patients with brain metastases suggest that microglia are the major immune population activated around the metastatic foci. Microglia and macrophages have the ability to polarize to different phenotypes and to exert both tumorigenic and cytotoxic effects. However, the role of microglia/macrophages during the early stages of metastatic growth in the brain has not yet been determined. The aim of this study was to profile microglial/macrophage activation in a mouse model of breast cancer brain metastasis during the early stages of tumor growth, and to assess the role of the anti-inflammatory microglial/macrophage population, specifically, during this phase. Following intracerebral injection of 5?×?103 4T1-GFP mammary carcinoma cells into female BALB/c mice, robust microglial/macrophage activation around the 4T1 metastatic foci was evident throughout the time-course studied (28?days) and correlated positively with tumor volume (R2?=?0.67). Populations of classically (proinflammatory) and alternatively (anti-inflammatory) activated microglia/macrophages were identified immunohistochemically by expression of either induced nitric oxide synthase/cyclooxygenase 2 or mannose receptor 1/arginase 1, respectively. Temporally, levels of both pro- and anti-inflammatory cells were broadly stable across the time-course. Subsequently, selective depletion of the anti-inflammatory microglia/macrophage population by intracerebral injection of mannosylated clodronate liposomes significantly reduced metastatic tumor burden (p?<?0.01). Moreover, increased levels of apoptosis were associated with tumors in clodronate liposome treated animals compared to controls (p?<?0.05). These findings suggest that microglia/macrophages are important effectors of the inflammatory response in the early stages of brain metastasis, and that targeting the anti-inflammatory microglial/macrophage population may offer an effective new therapeutic avenue for patients with brain metastases.

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Molecular pathways: VCAM-1 as a potential therapeutic target in metastasis.

Publications

Molecular pathways: VCAM-1 as a potential therapeutic target in metastasis.

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