Chemokine (C-C Motif) Ligand 2 Engages CCR2+ Stromal Cells of Monocytic Origin to Promote Breast Cancer Metastasis to Lung and Bone
ABSTRACT Metastatic spread of cancer to distant vital organs, including lung and bone, is the overwhelming cause of breast cancer mortality and morbidity. Effective treatment of systemic metastasis relies on the identification and functional characterization of metastasis mediators to multiple organs. Overexpression of the chemokine (C-C motif) ligand 2 (CCL2) is frequently associated with advanced tumor stage and metastatic relapse in breast cancer. However, the functional mechanism of CCL2 in promoting organ-specific metastasis of breast cancer has not been rigorously investigated. Here, we used organ-specific metastatic sublines of the MDA-MB-231 human breast cancer cell line to demonstrate that overexpression of CCL2 promotes breast cancer metastasis to both lung and bone. Conversely, blocking CCL2 function with a neutralizing antibody reduced lung and bone metastases. The enhancement of lung and bone metastases by CCL2 was associated with increased macrophage infiltration and osteoclast differentiation, respectively. By performing functional assays with primary cells isolated from the wild type, CCL2 and CCR2 knock-out mice, we showed that tumor cell-derived CCL2 depends on its receptor CCR2 (chemokine, CC motif, receptor 2) expressed on stromal cells to exert its function in promoting macrophage recruitment and osteoclast differentiation. Overall, these data demonstrated that CCL2-expressing breast tumor cells engage CCR2(+) stromal cells of monocytic origin, including macrophages and preosteoclasts, to facilitate colonization in lung and bone. Therefore, CCL2 and CCR2 are promising therapeutic targets for simultaneously inhibiting lung and bone metastasis of breast cancer.
- SourceAvailable from: Teresa Raposo
- "Blocking CCL2 in breast cancer cells impedes metastatic seeding, underpinning the role of the CCL2/C-C chemokine receptor type 2 (CCR2) axis in promoting breast cancer metastasis. Breast cancer cells secreting CCL2 induce monocyte-derived CCR2 + stromal cells to assist colonisation in the lung and bone, therefore facilitating metastasis (Lu and Kang, 2009). CCL2 expression is also upregulated in poorly differentiated breast cancers and supports the formation of tumour spheres in vitro, whereas loss of CCL2 delays tumourigenesis in cancer stem cells (CSCs) (Tsuyada et al., 2012). "
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- "A second cohort of lesser known anti-osteoclastogenic factors is also emerging for clinical trial. EGF signaling is able to induce RANKL and M- CSF secretion, and treatment with the EGFR kinase inhibitor Gefinitib suppresses osteoclast activity (Normanno et al., 2005) and inhibits bone metastasis (Lu et al., 2009). Similarly, small molecule antagonists of c-FMS can attenuate growth by 89% (Murray et al., 2003; Ohno et al., 2006). "
ABSTRACT: Bone metastasis is a frequent occurrence in late stage solid tumors, including breast cancers, prostate or lung. However, the causes for this proclivity have only recently been elucidated. Significant progress has been made in the past decade toward understanding the molecular underpinnings of bone metastasis, and much of this research reveals a crucial role of the host stroma in each step of the metastatic cascade. Tumor-stromal interactions are crucial in engineering a pre-metastatic niche, accommodating metastatic seeding, and establishing the vicious cycle of bone metastasis. Current treatments in bone metastasis focus on latter steps of the metastatic cascade, with most treatments targeting the process of bone remodeling; however, emerging research identifies many other candidates as promising targets. Host stromal cells including platelets and endothelial cells are important in the early steps of metastatic homing, attachment and extravasation while a variety of immune cells, parenchymal cells and mesenchymal cells of the bone marrow are important in the establishment of overt, immune-suppressed metastatic lesions. Many participants during these steps have been identified and functionally validated. Significant contributors include integrins, (αvβ3, α2β1, α4β1), TGFβ family members, bone resident proteins (BSP, OPG, SPARC, OPN), RANKL, and PTHrP. In this review, we will discuss the contribution of host stromal cells to pre-metastatic niche conditioning, seeding, dormancy, bone-remodeling, immune regulation, and chemotherapeutic shielding in bone metastasis. Research exploring these interactions between bone metastases and stromal cells has yielded many therapeutic targets, and we will discuss both the current and future therapeutic avenues in treating bone metastasis.Pharmacology [?] Therapeutics 10/2013; DOI:10.1016/j.pharmthera.2013.10.006 · 7.75 Impact Factor
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- "Similarly, overexpression of CCL2 in PC-3 prostate cancer cells led to increased bone metastasis associated with elevated accumulation of macrophages (Mizutani et al., 2009). Consequently, CCL2-neutralizing antibody treatment significantly prolonged survival of tumor-bearing mice due to inhibition of metastasis (Lu and Kang, 2009; Mizutani et al., 2009; Qian et al., 2011; Salcedo et al., 2000). Although elevated CCL2 expression is clearly linked to metastasis through the recruitment of monocytes/macrophages, the exact mechanisms by which CCL2 signaling facilitates tumor cell extravasation at the endothelial barrier and subsequent metastatic colonization remain elusive. "
ABSTRACT: Increased expression of the chemokine CCL2 in tumor cells correlates with enhanced metastasis, poor prognosis, and recruitment of CCR2(+)Ly6C(hi) monocytes. However, the mechanisms driving tumor cell extravasation through the endothelium remain elusive. Here, we describe CCL2 upregulation in metastatic UICC stage IV colon carcinomas and demonstrate that tumor cell-derived CCL2 activates the CCR2(+) endothelium to increase vascular permeability in vivo. CCR2 deficiency prevents colon carcinoma extravasation and metastasis. Of note, CCR2 expression on radio-resistant cells or endothelial CCR2 expression restores extravasation and metastasis in Ccr2(-/-) mice. Reduction of CCR2 expression on myeloid cells decreases but does not prevent metastasis. CCL2-induced vascular permeability and metastasis is dependent on JAK2-Stat5 and p38MAPK signaling. Our study identifies potential targets for treating CCL2-dependent metastasis.Cancer cell 07/2012; 22(1):91-105. DOI:10.1016/j.ccr.2012.05.023 · 23.89 Impact Factor