The role of the CX3CR1-FKN axis in tumor initiation and metastatic progression

Ramanpreet Kaur

doi:10.17918/00001000

Prostate cancer (PCa) is the second most frequently diagnosed cancer in men and its progression into metastatic disease is by far the major cause of death in these patients. Thus, it is essential to identify the molecular drivers of metastatic dissemination and to better define the role of the tumor microenvironment in the target organs, which allows the cancer cells to grow and survive at distant sites. Our lab has shown that PCa cells express the chemokine receptor CX3CR1 and are attracted to bone-derived CX3CL1 (or fractalkine/FKN), a membrane-bound ligand that can be cleaved to produce a soluble gradient, attracting PCa cells to the bone, in which they colonize and expand. Using FX-68, a novel CX3CR1 antagonist, we show that metastatic growth is decelerated when the receptor is inhibited. Studies show that most cancer cells grow within a tumor mass but lack the ability to form tumors upon spreading to other organs. In contrast, some cancer cells have the exclusive ability to both form new tumors and sustain their continuous growth. These tumor-initiating cells (TICs) are distinguished by their stemness features such as the ability to self-renew and resist therapy. Our lab has identified CX3CR1 as a novel marker of TICs, and treatment with FX-68 impairs tumor growth and increases the response to chemotherapeutics. The crosstalk between disseminated cancer cells and the surrounding bone microenvironment causes the production of growth factors, chemokines, and other inflammatory mediators promoting tumor growth. In particular, skeletal metastases harbor a significant contingent of macrophages, termed tumor-associated macrophages (TAMs), which are heavily implicated in promoting disease progression. We show that TAMs express CX3CR1 and depend on this receptor for migration into the tumor. Our studies indicate that pharmacologic antagonism of CX3CR1 not only causes an impairment of cancer cells' seeding and growth but affects also TAMs, limiting their infiltration of metastatic sites and in turn diminishing support to tumor growth. In summary, we show that the CX3CR1-FKN axis plays an instrumental role in metastatic PCa and provide evidence that its targeting represents a novel and potentially highly effective strategy to either prevent or treat PCa metastasis.

The role of the CX3CR1-FKN axis in tumor initiation and metastatic progression

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The role of the CX3CR1-FKN axis in tumor initiation and metastatic progression

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