The interaction between two specific proteins may be responsible for melanoma spreading, according to a new study.
This is the conclusion that researchers at the University of Tokyo in Japan reached after studying these molecules in cells and mice.
One of the molecules is called tissue plasminogen activator (tPA). This small protein functions as a protease, which is an enzyme that cuts up proteins.
The other molecule is a large protein called low-density lipoprotein receptor-related protein 1 (LRP1). LRP1 sits inside the membrane that surrounds animal cells, and tPA binds to it.
“It’s surprising,” says Dr. Beate Heissig, who is an associate professor in the Institute of Medical Science at the University of Tokyo and led this new research, “that LRP1 is also regulating cancer growth and spread. It’s normally a receptor for fat molecules.”
Melanoma and metastatic disease
According to the National Cancer Institute (NCI), there are more than 1.2 million people living with melanoma of the skin in the United States.
The NCI estimate that doctors will diagnose 91,270 cases of the disease in 2018 and that this figure will account for 5.3 percent of all new cancer diagnoses.
Rates of melanoma in the U.S. have risen steadily in the last couple of decades. In 1995, the number of newly diagnosed cases per 100,000 people was 16.5. By 2015, this figure had reached 25.8.
The most recent statistics for the U.S. suggest that 91.8 percent of people with melanoma will live for at least 5 years after diagnosis.
Based on NCI data from 2013–2015, approximately 2.3 percent of men and women will have melanoma of the skin at some stage in their lives.
Melanoma develops in melanocytes, a type of skin cell that makes melanin, which is a brown pigment that gives skin its color and protects its inner layers from sun damage.
Of the various forms of skin cancer, melanoma is the one that is most likely to spread to neighboring tissue and other places in the body. This tendency to spread, or metastasize, is what makes melanoma the most deadly type of skin cancer.
Cancer cells use proteases to create niches
In earlier work, Dr. Heissig’s team discovered that increasing tPA in mice boosted numbers of a cell type that often proliferates and spurs growth in melanoma tumors.
This finding led them to investigate tPA’s role as a protease in melanoma.
Metastasis is a complex process involving a series of steps. To spread through the body, cancer cells use a variety of tools and resources.
For example, once they reach new parts of the body, cancer cells use proteases to slash through the protein chains that anchor healthy cells to their place in the body.
This helps them carve out niches in which to start growing new tumors.
Attempts to prevent metastasis by blocking proteases have not been successful. No trial of a therapy that blocks these enzymes has had positive results.
Scientists suspect that preventing all protease activity also stops these enzymes from doing valuable jobs for healthy cells, which leads to harmful side effects.
Improving protease cancer treatment
“Our vision,” says first study author Dr. Yousef Salama, who works as a researcher in Dr. Heissig’s laboratory, “is a cancer therapy that specifically prevents the interaction of LRP1 and tPA so that only the metastasis effect of the protease is stopped.”
As a result of experiments in melanoma cells, the team reasoned that one way to stop tPA helping cancer cells to metastasize could be to prevent it from binding to LRP1.
They used a mouse model of melanoma to confirm this and found that mice lacking LRP1 had smaller tumors that did not grow even when the researchers gave the animals extra tPA.
“Better understanding of the specific interactions of LRP1 and tPA will hopefully lead to protease cancer treatments that maintain the normal, healthy protease actions of tPA.”
Dr. Yousef Salama