Potential Therapeutic Target Identified to Fight Metastasis in Ovarian Cancer

Potential Therapeutic Target Identified to Fight Metastasis in Ovarian Cancer

High levels of CXCR4, a receptor for signaling molecules that drive cell movement, allow ovarian cancer cells to grow faster and spread to other parts of the body, a study has found.

Researchers discovered that inhibiting CXCR4 prevents the dissemination and metastasis in the most aggressive type of ovarian cancer, revealing a new potential therapeutic target for this tumor type.

The study, “A Role for CXCR4 in Peritoneal and Hematogenous Ovarian Cancer Dissemination,” appeared in the journal Molecular Cancer Therapeutics.

Although several therapeutic advances have been made, about 70 percent of patients diagnosed with ovarian cancer will still have a recurrence, and the overall five-year survival rate is only 42 percent. This is mainly due to late diagnosis, when the cancer is already in an advanced stage and has spread to distant regions in the body.

That is the case for most patients with high-grade serous ovarian carcinoma (HGSOC), the most common and aggressive subtype of ovarian cancer.

Metastasis is dependent on a process called epithelial-to-mesenchymal transition (EMT), which allows cancer cells to detach from one another and enter circulation.

Chemokine receptors, such as CXCR4, have been associated with the migration of cancer cells and metastasis. They respond to chemokines, a family of secreted proteins that induce migration in cells expressing their receptors. CXCR4 is broadly expressed in immune cells, and is involved in their recruitment to inflammation sites.

In ovarian cancer, CXCR4 levels are known to increase with tumor stage and in patients with metastasis. However, the exact role of CXCR4 in those processes and in different types of ovarian cancer is not well-understood.

To clarify that, researchers in the Molecular Signaling in Cancer group of the Oncobell program (Bellvitge Biomedical Research Institute — IDIBELL) — proCURE Program (Catalan Institute of Oncology— ICO) investigated the role of CXCR4, using tumor and blood samples from women diagnosed with ovarian cancer.

Tumor samples were taken from 70 women with ovarian cancer, and blood samples from 38 ovarian cancer patients and 20 healthy women. A preclinical mouse model was used to study the development of patients’ tumors.

The levels of CXCR4 were significantly increased in HGSOC, compared with endometrioid carcinoma, a less aggressive ovarian cancer, confirming previous studies.

When CXCR4 was inhibited, tumor volume was reduced by 60% in HGSOC, compared with 30% in endometrioid carcinoma. This happened because tumor cells were dying more, and fewer new blood vessels were being formed. Aggressive tumors had higher levels of CXCR4, and researchers found that the more CXCR4 a tumor produced, the better the anti-tumor effects of inhibiting CXCR4.

Blood samples of ovarian cancer patients also showed higher levels of CXCR4 than healthy women, suggesting the presence of circulating tumor cells (CTCs), expressing CXCR4. CXCR4 inhibition reduced the number of CTCs and almost completely blocked the tumor’s ability to disseminate and generate metastasis.

“Our results identify for the first time a role for CXCR4 in inducing and maintaining CTCs present in blood,” the team said.

Researchers propose that CXCR4 activation leads to EMT of tumor cells and stimulates the generation of CTCs and their ability to migrate, which is associated with metastasis. CXCR4 inhibitors may be “therapeutic agents for the alternative or complementary treatment of advanced epithelial serous ovarian cancer patients,” they said.

“If we identify the factors that drive movement and implantation of tumor cells in new organs, we can try to block them in order to minimize the chances of metastasis,” Agnès Figueras, MD, first author of the study, said in a press release.