A team of researchers may have found a promising new route to fighting one of the world’s deadliest cancers. They have discovered a gene that plays a role in metastasis or cancer spread of a common lung cancer. The gene helps cancer cells pull up their anchors in the primary tumor and move easily to new sites where they form new tumors.
The team, from the Salk Institute in La Jolla, CA, reports its findings in the journal Molecular Cell.
Lung cancer is the leading cause of cancer-related deaths among Americans. According to the National Cancer Institute, nearly 160,000 people will die of lung cancer in the US in 2014, and the nation spends more than $12 billion on treatments for the disease.
Yet despite this massive amount of spending, lung cancer has an appalling survival rate. Within 5 years of diagnosis, 4 out of every 5 patients die – usually because the cancer spreads quickly to the rest of the body.
Researchers have so far established that for cancer to become mobile, cells in the primary tumor manage to overcome the normal cell’s ability to keep itself rooted to where it belongs. Normal cells do not travel.
Cancer cells become mobile because they have the ability to manipulate focal adhesion complexes – molecular protrusions that behave like anchors. In normal cells, the focal adhesion complexes keep them anchored in their proper locations in the tissue where they belong.
But cancer cells have the ability to “lift” their cellular anchors, leaving them free to travel via the bloodstream to other organs in the body and establish new tumors.
Previous studies have shown that various cancers have the ability to manipulate these anchors. They have also shown that in around a fifth of lung cancer cases, the patient is missing an anti-cancer gene known as LKB1 – that is also called STK11.
When the LKB1 gene is missing, the cancer is usually aggressive and spreads quickly to other organs. But, before this new study, nobody had linked LKB1 to focal adhesions.
The link was established with the help of another gene called DIXDC1. The team discovered that LKB1 communicates with DIXDC1, instructing it to change the size and number of the focal adhesions or anchors.
They found that when DIXDC1 is active, around half a dozen focal adhesions grow large and sticky and anchor their cells to the spot. When DIXDC1 is inactive or blocked, the large focal adhesions shrink and become hundreds of tiny “hands” that pull the cell forward in response to other signals. It is in this latter state that the cell is then free to travel to other sites.
First author and graduate student Jonathan Goodwin, says the “communication between LKB1 and DIXDC1 is responsible for a “stay-put” signal in cells. DIXDC1, which no one knew much about, turns out to be inhibited in cancer and metastasis.”
He and his colleagues found two ways to turn off the stay put signal – perhaps the cancer cell uses one of them. One way was to block DIXDC1 directly, and the other was to delete LKB1, which then fails to send the instruction to DIXDC1 to move to the focal adhesions and anchor the cell.
After showing these two methods the team then wondered if reactivating DIXDC1 could stop metastasis. They found it could. They took cancer cells that were spreading – so-called metastatic cells – found they had low levels of DIXDC1, and then overexpressed the gene.
The result was that switching DIXDC1 back on in metastatic cells did slow their ability to travel. They showed this in cultured cells and also in animal models.
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Mr. Goodwin says they were very surprised at how powerful the gene was:
“At the start of this study, we had no idea DIXDC1 would be involved in metastasis. There are dozens of proteins that LKB1 affects; for a single one to control so much of this phenotype was not expected.”
Senior and corresponding author Reuben J. Shaw, professor in Salk’s Molecular and Cell Biology Laboratory, says the reason some tumors spread easily and others do not has been poorly understood, but:
“Now, through this work, we are beginning to understand why some subsets of lung cancer are so invasive.”
Prof. Shaw, who is also a Howard Hughes Medical Institute early career scientist, explains that while currently there are no treatments for cancers with mutations in LKB1 or DIXDC1, it is likely that patients with either of the genes deleted would respond to drugs that target the focal adhesions.
Funds for the study came from the National Cancer Institute, the Howard Hughes Medical Institute, the Samuel Waxman Cancer Research Foundation, and the Leona M. and Harry B. Helmsley Charitable Trust.
Meanwhile in May 2014, Medical News Today learned how cancer spreads with help from bad cholesterol. In a study led by the University of Sydney in Australia, researchers found that high levels of bad cholesterol seem to help the integrins in cancer cells – the velcro-like molecules on the cell surface – to move around.