Inhibition of CXCR4-Mediated Breast Cancer Metastasis: A Potential Role for Heparinoids?

Abstract

Purpose: The pattern of breast cancer metastasis may be determined by interactions between CXCR4 on breast cancer cells and CXCL12 within normal tissues. Glycosaminoglycans bind chemokines for presentation to responsive cells. This study was designed to test the hypothesis that soluble heparinoid glycosaminoglycan molecules can disrupt the normal response to CXCL12, thereby reducing the metastasis of CXCR4-expressing cancer cells. Experimental Design: Inhibition of the response of CXCR4-expressing Chinese hamster ovary cells to CXCL12 was assessed by measurement of calcium flux and chemotaxis. Radioligand binding was also assessed to quantify the potential of soluble heparinoids to prevent specific receptor ligation. The human breast cancer cell line MDA-MB-231and a range of sublines were assessed for their sensitivity to heparinoid-mediated inhibition of chemotaxis. A model of hematogenous breast cancer metastasis was established, and the potential of clinically relevant doses of heparinoids to inhibit CXCL12 presentation and metastatic disease was assessed. Results: Unfractionated heparin and the low-molecular-weight heparin tinzaparin inhibited receptor ligation and the response of CXCR4-expressing Chinese hamster ovary cells and human breast cancer cell lines to CXCL12. Heparin also removed CXCL12 from its normal site of expression on the surface of parenchymal cells in the murine lung. Both heparin and two clinically relevant dose regimens of tinzaparin reduced hematogenous metastatic spread of human breast cancer cells to the lung in a murine model. Conclusions: Clinically relevant concentrations of tinzaparin inhibit the interaction between CXCL12 and CXCR4 and may be useful to prevent chemokine-driven breast cancer metastasis.Breast cancer metastases are commonly found in regional lymph nodes, bone, liver, and the lungs (1). Evidence shows that the sites of metastasis are determined not only by the characteristics of the cancer cells but also by the microenvironment of the specific organ (2). It seems that breast cancer cells are able to metastasize to specific organs in a manner that is dependent on the ability of the organ to mediate tumor cell adhesion and extravasation and to support subsequent viability and proliferation.Chemokines are members of a superfamily of chemotactic cytokines and were initially characterized because of their association with inflammatory responses. However, it is now known that they also play roles in homeostasis, cell proliferation, hematopoiesis (3), viral interactions, angiogenesis, and neovascularization (4). Four chemokine classes have been defined based on the location of the first two cysteine residues in the protein sequence (CXC, CC, C, and CX 3 C). CXCL12 (stromal cell -derived factor-1a) is a CXC chemokine and is the sole ligand for the receptor CXCR4, although CXCL12 can also signal through the orphan receptor RDC1 (CXCR7) on T lymphocytes (5). Chemokines activate members of the seven-transmembrane spanning G protein -coupled receptor family. On chemoki...

Technical Advance: Surface plasmon resonance-based analysis of CXCL12 binding using immobilized lentiviral particles

“…Our results are also consistent with results using 125 I-CXCL8 and 125 I-CCL3 with CXCR1-, CXCR2-, or CCR1-transfected CHO cell membranes [36], as well as with data from various laboratories showing that soluble heparin and heparan sulfate inhibit leukocyte responses [40,42]. Unfractionated heparin and the low MW heparin Tinzaparin inhibit CXCL12 binding to CXCR4-expressing CHO cells and human breast cancer cell lines, thus blocking signaling; these compounds might be useful in preventing chemokinedriven breast cancer metastasis [43].…”

Omega-3 Polyunsaturated Fatty Acids Down-Modulate CXCR4 Expression and Function in MDA-MB-231 Breast Cancer Cells

“…Overexpression of chemokine receptors or ligands can lead to enhanced survival, migration, and unchecked growth of the tumor cells (6). Some current therapies are designed to block the up-regulated chemokine receptors as a treatment for cancer and cancer metastasis (7,8).…”

Chemokine (C-X-C Motif) Ligand 12 Is Associated with Gallbladder Carcinoma Progression and Is a Novel Independent Poor Prognostic Factor

“…These observations suggest that CXCL12 promotes the growth and tumorigenicity of GBC through interaction with CXCR4. CXCL12 is involved in cell migration, invasion, and adhesiveness in several types of cancer (13,22,23,27). In this study, GBC cells showed enhanced motility and invasiveness in response to CXCL12.…”

“…It has been shown that CXCL12 is closely involved in motility, invasiveness, adhesiveness, and survival of several types of tumors (13,22,27). To address this issue, we also examined the effect of CXCL12 on motility and invasiveness of GBC cells using Transwell filter assays.…”

“…CXCL12 activates its receptor CXCR4, which is involved in cell proliferation, migration, and invasion (13,14), and thus promotes organ-specific localization of distant metastases of various carcinomas (15)(16)(17). Blocking the interaction between CXCR4 and CXCL12 by CXCR4 antagonists inhibits the number or size of tumor metastases (18)(19)(20)(21)(22)(23)(24). However, the mechanisms by which CXCL12 exerts its metastatic effects are unknown.…”