Scientists at VIB and KU Leuven have shown that reducing the expression of the PHD2 oxygen sensor impairs the ability of breast cancers to metastasise (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 tumours 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 tumour models, blocking PHD2 expression does not promote tumour 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 normalising tumour vessels and by de-activating “cancer-activated fibroblasts”.

In tumours, 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 neighbours, the cancer-activated fibroblasts.

In fact, not a single therapy exists to de-activate these fibroblasts and thereby counteract metastasis.

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 tumours 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 neighbouring 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 (anaemia 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 honoured Dr. Carmeliet for his years of dedication to unravelling 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 recognise 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.

Source: VIB