Blocking the PHD2 oxygen sensor inhibits breast cancer dissemination

30 July 2015
​Scientists at VIB and KU Leuven have shown that reducing the expression of the PHD2 oxygen sensor impairs the ability of breast cancers to metastasize (spread) to other parts of the body. Breast cancer is the second leading cause of cancer death in women, primarily due to metastasis. These findings indicate that PHD2 inhibition may have valuable therapeutic potential. The study was published in the leading medical journal Cell Reports, which features cutting-edge biological research.

The study is the first to examine the effect of blocking PHD2 expression in a spontaneous breast cancer model, which more closely mimics human cancer than the transplantable tumors used in previous research. The study also discovered an unexpected role for stromal fibroblast cells, cells that support cancerous tissue and promote cancer cell dissemination.

Global PHD2 inhibition safely reduces metastasis
A research team led by Peter Carmeliet (VIB/KU Leuven) discovered that genetic blockade of PHD2 substantially reduced breast cancer metastasis, the primary cause of death of breast cancer patients. Despite improvement in breast cancer therapy, the development of an efficient therapy to halt breast cancer metastasis is still a large unmet medical need. Their research also showed that, contrary to inconsistent results from previous experiments in suboptimal tumor models, blocking PHD2 expression does not promote tumor growth and is thus a safe therapeutic approach.

Shutting down cancer’s escape routes
The study showed that PHD2 inhibition reduced metastasis through two novel mechanisms: by normalizing tumor vessels and by de-activating “cancer-activated fibroblasts”. In tumors, the support fibroblast cells become highly activated and lay down connective support tissue, which cancer cells use as “highways” to travel on to escape to distant organs. However, most anti-cancer therapies have been focused on targeting the malignant cancer cells, not their neighbors, the cancer-activated fibroblasts. In fact, not a single therapy exists to de-activate these fibroblasts and thereby counteract metastasis.



Caption: immunostaining for markers of CAFs (cancer-associated fibroblasts) (visible in red and green) on the tumor sections of spontaneously arising breast tumor model we have used in our study


Peter Carmeliet (VIB/KU Leuven): “We found that blocking the PHD2 oxygen sensor reduces the spread of breast cancer in two ways: first, it helps blood vessels in tumors to return to their normal, stronger state, reducing the opportunity for cancer cells to escape through the vessel wall. Second, it stops cancer cells from highjacking neighboring activated fibroblast cells and instructing them to build highways of connective support tissue that the cancer cells can use to migrate into other areas of the body.”

PHD2 blockers are currently being tested in the clinic for the treatment of blood disorders (anemia or bloodlessness).

The research, which appeared in the July 2015 issue of Cell Reports, opens the door to further studies exploring the therapeutic potential of PHD2 inhibition in treating human breast cancer.

Royal recognition for groundbreaking cancer research
Earlier this month, Belgium’s royal monarch honored Dr. Carmeliet for his years of dedication to unraveling the mysteries of cancer and the role new blood vessel formation (angiogenesis) in this deadly disease.

Frans van Daele (cabinet chief to King Philip of Belgium): “His Majesty is pleased to recognize Dr. Carmeliet’s role as a scientific pioneer and ambassador, and his dedication to promoting high-quality research that can lead to the clinical development of lifesaving therapies to the benefit of society.”

A humbled Baron Carmeliet—as he may now call himself—says he plans to continue investigating the mechanisms that drive cancer for many years to come.

Publication
The Cancer Cell Oxygen Sensor PHD2 Promotes Metastasis via Activation of Cancer-Associated Fibroblasts, Kuchnio et al., Cell Rep. 2015


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Peter Carmeliet is organizer of the VIB conference
'Metabolism in Cancer and Stromal Cells'



Peter Carmeliet (c) De Standaard


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