The Role of Chemokines in Cancer

Breast Cancer

The leading cause of death in cancer patients is from metastasis, the formation of secondary tumors in organs distant from the original tumor. It is not a random process but rather shows bias for particular tissues, which is due in part to chemokine-receptor interactions. For example, the chemokine receptor CXCR4 is not expressed on normal breast epithelia but is frequently expressed on breast cancer cells which have a tendency to metastasize to lymph node, bone marrow, lung and liver, sites where the ligand, CXCL12, is constitutively expressed (see Figure). Additionally, there is emerging evidence that chemokine receptor signaling in cancer cells does more than facilitate cell migration, and may promote growth and survival of the cells in the foreign environment of a metastatic lesion. However, the exact mechanisms by which CXCR4 and other receptors enhance metastasis and/or tumor growth is not well-understood. We are using cell based assays, in vivo experiments and proteomics to study role of CXCR4, as well as another receptor, CXCR7, in breast cancer.

This figure illustrates many aspects of cancer progression where chemokines/receptors play a role: growth of the primary tumor, angiogenesis (cell migration of endothelial precursors), metastasis (migration of primary tumor cells to secondary sites), and growth/survival of the metastasized cells. For a review on this subject, click here.

Chronic Lymphocytic Leukemia

B cell chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature, monoclonal B cells in the blood, secondary lymphoid tissue, and bone marrow. Their accumulation appears to be due to resistance to apoptosis and responsiveness to survival signals. However, despite their extended survival in vivo, CLL cells rapidly undergo apoptosis in vitro unless rescued by accessory cells including "Nurse-Like Cells" (NLCs) derived from the microenvironment. The CLL cells secrete factors that induce differentiation of monocytes into NLCs; in turn, the NLCs provide CLL cells with survival factors that protect them from spontaneous and therapy-induced apoptosis in vitro. Thus, it has been postulated that the microenvironment plays a significant role in the accumulation of CLL cells in vivo by providing protective niches where NLCs secrete survival factors that prolong the longevity of CLL cells and limit the effectiveness of therapeutic agents. The goal of our research in this area is to characterize the two-way molecular communication between CLL cells and NLCs, and to understand how their interplay contributes to disease progression and aggressiveness. Identifying the proteins secreted by NLCs, and the downstream signaling pathways induced by these factors in CLL cells, will likely reveal novel therapeutic targets. For example, we have been using a combination of directed immunoblot and global proteomic profiling approaches, to determine the molecular mechanisms underlying CXCL12-induced survival signaling and potential differences in signaling between CLL cells from patients with an aggressive form of the disease compared to those from patients with indolent disease. For a recent publication, click here

Techniques: Cell Biology and Signaling, Proteomics, In Vivo Studies