‘Something weird’ may lead to melanoma breakthrough

Source: Western News,  July 2015

Western researchers look to take metastatic melanoma survival rates from a gloomy 5 per cent five years after diagnosis to almost 100 per cent, by simply looking where others haven’t.

“We decided to do something weird. We focused on the things nobody knew anything about, looked at things in a slightly different fashion,” said Schulich School of Medicine & Dentistry professor Andrew Leask.

Melanoma, the second most common invasive cancer in young adults, is the most dangerous form of skin cancer. Mole-like growths develop when unrepaired DNA damage to skin cells (most often caused by ultraviolet radiation from sunshine or tanning beds) triggers mutations, or genetic defects, that lead the skin cells to multiply rapidly and form malignant tumours.

It is estimated 6,800 Canadians will be diagnosed with melanoma in 2015, with 1,150 dying from the disease. One in 57 men and 1 in 74 women are expected to develop melanoma during their lifetime.

While not the most common skin cancer, it is the deadliest, Leask said. However, if melanoma is recognized and treated early, it is almost always curable. If allowed to grow unchecked, however, the cancer can spread to other parts of the body, such as the lungs and bones, where it becomes hard to treat and is often fatal.

Most researchers are focused on BRAF, a human gene that makes a protein called B-Raf, which is involved in sending signals and directing cell growth in the body. A class of drugs that targets BRAF are used to block tumour proliferation, but patients eventually acquire resistance to these drugs and metastasis occurs anyway.

However, when Leask and his fellow researchers looked at “things in a slightly different fashion,” they made an interesting discovery: It was the surrounding tissue (formally called cancer-activated fibroblasts) instructing cells to metastasize and invade surrounding tissues.

“It’s not just the melanoma cells that are the problem, but the surrounding tissues,” said Leask, a professor in Physiology and Pharmacology and Dentistry. “People have known there is surrounding tissue. No one actually looked at why it was important. This is the first proof it is important and the first proof these proteins are triggering cancer cells to behave badly.”

If you consider the melanoma as some weird stem cell, he said, what they are doing is secreting stuff into the environment that’s activating the cells, called fibroblast, or cancer-activated fibroblasts.

“These guys are now producing signals instructing the melanoma cells how to behave,” he continued. “The kicker is we found the mechanism of how this does that.”

That mechanism is due to the expression of two proteins – CCN2 and periostin. Therefore, drugs blocking CCN2 or periostin would represent a new drug treatment targeting melanomas.

“The tissues are cross-talking. It’s more the surrounding tissue that is instructing the how the stem cells should behave,” he said. “If you blocked this communication, you will be able to block this whole process. It’s actual proof that it’s more the surrounding tissue instructing the bad stem cells to behave.”

By not allowing the melanoma to metastasize, it can be removed far easier through surgery.

“Survival rate should be awful close to 100 per cent,” Leask said.

Leask published the findings in the Journal of Investigative Dermatology, along with co-investigators James Hutchenreuther, MSc candidate; Krista Vincent, Anatomy and Cell Biology MD/PhD candidate; David Carter, Robarts Research Institute scientist and London Regional Genomics Centre; and Lynne-Marie Postovit, formerly of Western’s Department of Anatomy and Cell Biology, currently of the Department of Oncology at the University of Alberta.

The team will continue their work, through clinical samples and animal models, to specifically prove the fibrotic tissue is causing or instructing the melanoma. Through a strong collaborative effort he expects clinical data could be completed within three years.