Targeting chemokines in breast cancer

Abstract

American and French researchers have identified CXC chemokine receptor 1 as a new target for blocking the formation of breast cancer stem cells that drive tumor growth and metastasis. 1 The findings could represent a repurposing opportunity for Italian biotech Dompe Farmaceutici S.p.A., which is exploring new indications for its small molecule inhibitor of the receptor after the compound missed the primary endpoint in Phase II transplant dysfunction trials.The therapeutic rationale for targeting cancer stem cells is clear: deplete the subset of cancer cells with the ability to self-renew and generate the full range of cells that make up a bulk tumor 2 so the disease cannot progress or relapse. The challenge has been identifying druggable targets unique to cancer stem cells.Researchers at the University of Michigan and the Institut National de la Santé et de la Recherche Médicale (INSERM) have used gene expression profiling to identify a breast cancer stem cell signature. 3 In 2009, the team found that CXC chemokine receptor 1 (CXCR1) was among the genes almost exclusively expressed in the cancer stem cell population compared with its expression in bulk tumor cells.CXCR1 is a receptor for IL-8 (CXCL8), a proinflammatory chemokine that has been implicated in the metastasis and progression of multiple malignancies, including glioma and prostate, breast and ovarian cancers. 4-7 IL-8 has also been shown to stimulate self-renewal of breast cancer stem cells in vitro. 2 The UM-INSERM team now has taken the next step and studied the effects of small molecule and antibody antagonists of CXCR1.In a human breast cancer cell line, both the small molecule CXCR1 inhibitor reparixin and an anti-CXCR1 antibody reduced the number of breast cancer stem cells compared with no treatment.After four days, both molecules abolished the entire cancer cell population even though CXCR1-expressing stem cells comprised about 2% of the total. That result suggested that CXCR1 blockade directly decreased the survival of cancer stem cells and indirectly induced cell death in the bulk tumor population.Mechanistic studies showed that inhibiting CXCR1 induced the production of soluble Fas ligand (TNF superfamily, member 6; FASL) by cancer stem cells. The proapoptotic FASL then bound its receptor on bulk tumor cells, triggering apoptosis and cell death (see Figure 1, "Chemokine blockade in breast cancer").In mice with primary human breast cancer xenografts, reparixin alone or in combination with docetaxel reduced tumor growth compared with saline control. The combination had greater efficacy than either reparixin or docetaxel alone.Additional experiments showed that reparixin could reduce cancer metastasis. Three groups of mice were injected with breast cancer cell lines. The animals then received reparixin twice daily for 28 days. At the end of that period, two of the three groups showed significant reductions in metastasis compared with animals that received saline control (p<0.01).The team was led by Max Wicha, professor of oncology and intern...

Cancer stem cells: a challenging paradigm for designing targeted drug therapies

“…There are various types of stromal cells, such as tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and endothelial cells, which are usually in direct contact with tumor cells and help these cells to maintain their stemness, thereby facilitating tumor progression [73]. The cellular and molecular factors that have important roles in mediating communication between tumor cells and TME include cytokines [e.g., interleukin (IL)-6, IL-8, transforming growth factor (TGF)-β, and oncostatin M (OSM)] [76][77][78], chemokines [e.g., CXC chemokine receptor 1 and 4 (CXCR1 and CXCR4)] [79,80], and growth factors, such as EGF and b-FGF (basic fibroblast growth factor) [81], which are crucial for tumor growth and survival. It has also been shown that IL-6, IL-8, and OSM, which are secreted by TAMs and CAFs, are responsible for the stemness ability of tumor cells.…”

Identification and Functional Study of Cytokines and Chemokines Involved in Tumorigenesis

“…Recently it was found that CXCL8 could stimulate self-renewal of breast cancer stem cells in vitro by binding its receptor CXCR1 which is almost exclusively expressed in the cancer stem cell population compared with bulk tumor cells [83,84]. In human breast cancer cells, both an anti-CXCR1 antibody and the small molecule CXCR1 inhibitor reparixin could abolish the entire cancer cell population even though CXCR1-expressing stem cells only comprised about 2% of the total, suggesting that CXCR1 blockade directly decreased the survival of cancer stem cells and indirectly induced cell death in bulk tumor population.…”

“…Mechanistic studies showed that inhibition of CXCR1 induced the production of soluble Fas ligands (TNF superfamily, member 6; FASL) by cancer stem cells. The proapoptotic FASL then bound its receptor on bulk tumor cells, triggering apoptosis and cell death [83].…”