Fat cells (depicted here) may be essential for the survival of cancer cells.
Cancer is an increasingly complex area of study, with every perceivable angle of attack being plumbed by researchers.
Despite millions of hours of experimentation, however, there are still many questions left unanswered.
As we learn more about cancer, it becomes more and more clear that it needs to be approached as a whole-body disease.
For cancer to survive and thrive, it needs to draw energy from the body's cells and tissues, utilize the circulatory system, and avoid the immune system. Tumors need to work intelligently to sustain their growth and become integrated in the body.
Researchers are now focusing on attacking not just the cancerous cells, but also the systems that tumors rely on to sustain them.
Tumor, metabolism, and fat
Researchers from Sanford Prebys Medical Discovery Institute in San Diego, CA, are now particularly interested in the way that tumors communicate with fat cells. Co-senior study author Maria Diaz-Meco, Ph.D., explains further.
"We need to consider," she states, "other aspects of cancer therapeutics beyond the better-known genetics. That is, we need to invest more in the research of cancer metabolism, which deals with the identification of metabolic vulnerabilities that should be common to all types of cancers."
This line of investigation is vital. As Diaz-Meco continues, "This will ultimately lead to better therapies that are less susceptible to resistance, which is an all-too-common problem in oncogene-target approaches."
In the United States, prostate cancer is the second leading cause of cancer-related death among men. Obesity is known to be a major risk factor and predicts how aggressively the cancer will behave. But exactly how obesity worsens prostate cancer outcomes is not yet known.
To date, many studies exploring obesity and prostate cancer have focused on mice that have been fed a high-fat diet. Co-senior study author Jorge Moscat, Ph.D., explains why this is not ideal.
"Although this mimics some of the situations in patients," he says, "it prevents a real understanding of the signaling pathways that control the bidirectional communication between tumors and adipocytes, or fat cells."
"This is essential," adds Moscat, "if we want to identify therapeutic targets that can be harnessed to prevent the pro-tumorigenic signals emanating from the adipose tissue."
Moscat and Diaz-Meco approached this problem from a new direction: they used a mouse model that lacks a particular protein known as p62 in its fat cells. Mice deficient in this protein become obese even when fed a standard diet.
Their intriguing findings are now published in the journal Cancer Cell.
Tumors use fat cells for fuel
They found that p62 plays an important role in the communication between fat tissue and tumors. The protein appears to support the "metabolic fitness" of cancer, promoting progression and metastasis. It achieves this by inhibiting a second protein called mTORC1.
When mTORC1 is suppressed, so are the energy-consuming activities of fat cells, such as oxidative phosphorylation and "fatty acid metabolism in white fat tissue." With these processes halted, there are more fatty acids and other nutrients available for the tumor to use to grow and develop.
"This metabolic reprograming orchestrated by the loss of p62 in adipocytes appears to help tumors cope with the high-energy demands of an aggressive cancer."
Maria Diaz-Meco, Ph.D.
In follow-up experiments, the team demonstrated that a lack of p62 also promotes the production of Cpt1a and osteopontin, both of which help cancer cells to proliferate and metastasize.
In particularly aggressive, castration-resistant prostate cancer, Cpt1a and osteopontin are found in higher levels.
These findings will be relevant to future treatments of cancer. As Moscat says, "The significance is huge because we identify a new set of therapeutic targets that, if modulated, should block the ability of activated adipose tissue to promote tumor malignancy."
Today, mTOR inhibitors are used to treat a number of cancers. The researchers are concerned that this could shut down fat tissue metabolism, however, thereby fueling tumor growth in some cases.
However, more studies will be needed to confirm whether this is the case.