One of the most challenging aspects of cancer is its ability to metastasize.
Cancer cells can break away from their current position, travel through the body, and begin multiplying in new, distant locations.
Metastasis makes tumors difficult to find and to treat. Since metastasis is such a pivotal area of cancer research, scientists put a great deal of work into understanding how cancer does it.
A recent study, carried out by Michael J. Morgan, Ph.D., at the University of Colorado Cancer Center in Aurora, adds new detail to an already complex picture. The findings are published in the Proceedings of the National Academy of Sciences.
The scientists were particularly interested in cellular garbage disposal. Morgan explains why this is, saying, "Highly metastatic cells leave their happy home and have all these stresses on them. One way that the cell is able to deal with stresses is through disposing of cellular wastes or damaged cell components and recycling them."
If one interferes with this recycling process, metastasis can be blocked.
"When we turn off the activity of cellular structures called lysosomes," says Morgan, "which a cell uses to do this recycling, the metastatic cells become unable to survive these stresses."
Important in this recycling is autophagy, a natural process wherein the cell breaks down and recycles faulty parts of the cell.
Morgan and Andrew Thorburn — who helped with the recent research — are both considered experts on the topic of autophagy. Also involved was Dr. Dan Theodorescu, an expert in metastasis.
The process of autophagy
Autophagy is essential for the survival of healthy cells and malignant cells alike. In basic terms, autophagy begins when cellular "rubbish" is surrounded by a spherical structure called an autophagosome.
This double-membraned structure carries the rubbish through the cytoplasm until it reaches a package of destructive enzymes known as a lysosome. The autophagosome fuses with the lysosome and the contents are destroyed.
By tinkering with this process, Morgan and team uncovered ways to interfere with a cancerous cell's ability to metastasize.
"What was surprising," says Morgan, "was that it was not the process of autophagy itself that was specifically important for the metastatic cell. If you inhibit autophagy at an early stage, you can reduce the cell growth of both metastatic and non-metastatic cells."
"But if you block the lysosome function of late-stage autophagy, it hits these metastatic cells a lot harder, and they actually die."
Michael J. Morgan, Ph.D.
In other words, when the team blocked autophagy by genetically switching it off, both metastatic and non-metastatic cells suffered. However, when they inhibited autophagy and lysosomes with the drug chloroquine, non-metastatic cells were slowed down a little, but metastatic cells were completely destroyed.
"There was something about lysosomes that was specific to these metastatic cells," says Thorburn.
Why are lysosomes so important?
Next, the scientists wanted to drill down and understand exactly why lysosomes are so incredibly important to metastasizing cancer cells. To do this, they developed chloroquine-resistant cells.
This involved growing metastatic cells alongside small quantities of chloroquine. Most of the cells died, but those that survived were kept and grown again with chloroquine. As they divided many times, each successive generation became increasingly resistant to chloroquine.
However, as the cells steadily became resistant, they lost their ability to metastasize.
As Morgan explains, "The door swings both directions: when we selected for cells that resisted chloroquine, they became non-metastatic. And when we selected for cells that were metastatic, they gained sensitivity to chloroquine. They stopped growing and they died because, all of a sudden, they came to depend on the lysosomal action that chloroquine takes away."
This finding may be useful in the treatment of cancer. Theodorescu gives an example, saying, "With a patient, if they had a bladder cancer tumor and we gave chloroquine, let's suppose that some cancer cells became resistant to chloroquine."
"We would predict, based on our study, even if the resistant cells start to grow again, they wouldn't be metastatic anymore. This may have clinical benefit for the patient."
Lastly, the researchers found that a protein called ID4 seems important in this process. Cells with lower levels of ID4 were sensitive to chloroquine and metastatic; those with higher levels of ID4 were less metastatic and chloroquine-resistant.
It is possible that ID4 could be used as a marker to predict patient outcomes. In fact, higher levels of ID4 are already known to predict better outcomes for bladder, breast, and prostate cancer.
Currently, there is a great deal of interest in autophagy inhibitors for use in cancer treatment; this study provides an interesting insight, and will no doubt inspire further investigation.