Hypoxia-inducible factor 1 (HIF-1) and platelet-derived growth factor B (PDGF-B) may represent promising therapeutic targets for preventing breast cancer from spreading to the lymph nodes and metastasizing to other organs, scientist claim. Emerging data from human patients have linked activation of HIF-1 with tumor angiogenesis, metastasis, and mortality, but the protein’s role in lymphatic dissemination of cancer hasn’t been well understood. Now researchers at the Johns Hopkins University School of Medicine and partners in Italy have found that HIF-1 promotes lymphatic metastasis of breast cancer directly by activating the gene encoding PDGF-B, which triggers the growth of new lymphatic vessels.

Previous work by Gregg L. Semenza, M.D., and colleagues had shown that knocking out HIF-1α or HIF2α in mice implanted with human breast cancer cells (BCCs) slowed tumor growth and lung metastasis. Treating animals with the HIF-1 inhibitor digoxin similarly impaired primary tumor growth and lung metastasis. Initial studies in the team’s latest round of research showed that mice injected with HIF-1 knockdown human BCC cells exhibited 76% fewer cancer cells in their lymph nodes after 24 days than animals injected with unengineered BCC cells, supporting a role for HIF-1 in the spread of breast cancer to lymph nodes.

With these results in mind, the investigators looked more closely at the effects of HIF function and loss on lymph node (LN) metastasis and lymphatic vessel (LV) density. Their experiments found that HIF-1 binds directly to the gene for PDGF-B, which is overexpressed under the hypoxic conditions found in tumors, and triggers the growth of lymphatic vessels. This notion of direct binding of HIF-1 to the PDGF-B gene was supported by immunohistochemical analyses demonstrating that HIF-1 and PDGF-B colocalized in human tumors in mice. Moreover, coexpression of HIF-1α and PDGF-B was also found in invasive breast carcinomas, and this coexpression correlated with LV area and the histological grade of tumor according to the Scarff–Bloom–Richardson scale, which is an important predictor of patient survival and response to chemotherapy, the researchers stress.

The researchers’ analyses indicated that PDGF-B produced as a result of HIF-1 binding is released from the tumor cells and binds to its cognate receptor PDGFRβ, which is upregulated on lymphatic endothelial cells (LEC) under hypoxic conditions. This PDGFβ signaling triggers LEC proliferation and migration, and the growth of lymphatic vessels. When the researchers turned off PDGFRβ signalling by blocking HIF-1 or PDGF-B using either RNA interference, or chemical inhibitors (digoxin or the tyrosine kinase inhibitor imatinib), both lymphatic vessel density and lymph node metastasis were significantly reduced.

Reporting their findings in PNAS, the investigators say that as well as highlighting HIF-1 and PDGF-B as potential therapeutic targets for breast cancer, their results suggest that co-expression of the two proteins may help to identify lymph node-negative patients who are at a high risk for developing lymph node metastasis, and who could benefit from treatment using drugs that target one or both of the implicated factors. The first study of digoxin in women with breast cancer is due to start at the Johns Hopkins Oncology Center later this year. Professor Semenza et al., describe their findings in a paper titled “Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells.”

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