Fight Aging!

This popular science article looks at opposing views of the role of macrophages in the development of tumors. Some groups see macrophages as aiding the cancer, and want to suppress them, while others are engaged in turning macrophages into an effective weapon to destroy cancer cells. This two-faced nature echos a range of unrelated work on macrophage behavior. These cells can be classed by their activities into what are known as polarizations. The M1 polarization is aggressive and inflammatory, willing to attack cells and pathogens, while the M2 polarization aids tissue growth and regeneration. The balance between the two shifts according to circumstances. Both are necessary, but M1 is too prevalent throughout the body in older individuals, hindering tissue maintenance. In cancers, the problem is reversed: too many M2 macrophages are present to help the cancer, while too few M1 macrophages actively attempt to destroy its cells.

In the late 2000s, researchers found that leukemia cells highly expressed a gene encoding CD47, a surface molecule known for its role on normal, healthy cells as a "don't eat me" signal to phagocytosing macrophages. Researchers demonstrated in cell culture experiments that macrophages only engulfed leukemia cells that did not display CD47 on their surface, and since then have found CD47 on every type of cancer they've been able to get their hands on. "It was shocking. We knew that we were on the track of a potential therapeutic." At least three biomedical companies have raised and invested tens of millions of dollars to test drugs that block CD47.

But back in 2008, when the researchers first tried to publish work on how macrophages engulfed leukemia cells lacking CD47, reviewers didn't buy it. Since the 1980s, cancer researchers have linked macrophages and macrophage-stimulating genes to tumor growth and poor outcomes for cancer patients, and the cells had been pegged as nothing but bad news when it came to cancer. In 1996, for example, researchers reported that women whose breast cancer biopsies contained a high density of macrophages were much more likely to succumb to the disease over the subsequent five years than those with low densities. The same correlation was later confirmed in a dozen other types of cancer. These cells earned the name tumor-associated macrophages, or TAMs, and research focused on where they came from and how to block or deplete them. The data suggesting that macrophages could help defeat cancer just didn't fit.

TAMs, which can make up as much as 50 percent of a tumor's mass, had been found to repress other immune cell activity, encourage blood and lymph vessel development to support growing tumors, and help cancer cells metastasize to new sites in the body. But over the past decade, some research has surfaced to support the conclusion that TAMs may have an upside. "Several years ago, the idea was, 'Let's deplete these cells because they are bad.' I think now we are back to saying, 'Maybe it's just very complex.'"

Even as therapies that block TAM activity or prevent macrophage recruitment to tumors reach clinical trials, many researchers are not ready to give up on what macrophages may have to offer in the fight against cancer. There's no question that macrophages can participate in antitumor responses, "it's just that the tumors develop a way of polarizing or educating those macrophages to help the tumors rather than destroy them." Many researchers are now taking advantage of macrophages' plasticity to re-educate the cells to work for the patient. One way to switch TAMs from what's known as the M2 phenotype, which promotes cancer growth, to the immune-boosting M1 phenotype is to provide the cells with proinflammatory stimuli, such as interferons or ligands for Toll-like receptors. Alternatively, researchers can directly target molecular switch proteins responsible for driving M2 characteristics, such as PI3-kinase and the transcription factor STAT3. In animal models, drugs that inhibit these molecules have successfully skewed TAMs toward M1 phenotypes and shrunk tumors.

Link: https://www.the-scientist.com/?articles.view/articleNo/52134/title/Macrophages-Play-a-Double-Role-in-Cancer/