The Role of Adipose Tissue in Cancer Aggressiveness

A Conversation With Mikhail Kolonin, PhD

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Over the past decade, obesity has been linked to an increased risk and aggressiveness of numerous cancer types. Many biologic activities within adipose tissue change with obesity and may contribute to carcinogenesis and the initiation of cancer. To shed light on the current state of knowledge in this intriguing line of inquiry, The ASCO Post spoke with Mikhail ­Kolonin, PhD, Professor and Harry E. Bovay, Jr, Distinguished University Chair in Metabolic Disease Research at McGovern Medical School, The University of Texas Health Science Center, Houston.

Mikhail ­Kolonin, PhD

Mikhail ­Kolonin, PhD

Adipose Tissue and Carcinogenesis

Please tell the readers about your current research.

My lab works on adipose tissue, cancer biology, and the interplay between both systems. Our work, based on the analysis of clinical specimens and mouse models, focuses on the role of fat tissue cells in healthy aging and disease. We have discovered the phenomenon of adipose cell mobilization and trafficking to tumors and the stimulatory effect of adipose stromal cells on cancer progression.

The human body has essentially two types of fat tissue: white and brown. We are born with mostly brown adipocytes, packed with mitochondria, which burn energy and produce heat that defends us against hypothermia, obesity, and diabetes.

As we grow older and gain weight, we begin losing our brown fat cells and increase the number of lipid-storing white fat cells. If you ingest excess calories, white adipocytes enlarge their lipid stores and increase in number. With that, there is also an increase in the risk of a number of diseases, one being cancer.

Please describe how genotoxic stress evolves and its role in carcinogenesis.

Cancer develops as a result of cellular damage from being bombarded by stressors, some of which are environmental and some of which are internal, such as inflammation. These various exposures and stressors can produce free radicals that injure molecules in our cells—proteins, lipids, and nucleic acids. Also, free radicals generated by mitochondria, or from other sites within or outside the cell, cause damage to cellular components and contribute to oxidative stress.

Generating free radicals is vital for normal cell function; however, too many free radicals creates a problem. Extensive overeating contributes to excessive free radicals, which cause oxidative damage to the cell’s organelles. Genotoxic damage is a specific type of oxidative damage in the chromosomal DNA that can lead to cancer initiation.

Possible Obesity Therapy?

You have suggested a therapeutic approach to shrinking blood vessels in fat by starving the fat cells. Please explain.

One of our papers showed that fat tissue relies on blood vessels, much like tumors. In short, once you deprive tumors of their blood supply by shrinking the blood vessels, the tumors die. So, we postulated that the same mechanisms could be employed to destroy the blood vessels that support fat accumulation, causing adipose tissue to rapidly break down and disappear.

We have developed an experimental compound that enables us to look at tumor–fat tissue interaction in animal models. When you inject that agent [prohibitin-TP01] into mice, it hones in on and promotes the death of blood vessels associated with white fat tissue, which is then reabsorbed and metabolized.

We found that 1 month of treatment in severely obese mice was enough to restore the animal’s normal body weight. None of the mice used in the experiment were genetically altered or prone to obesity prior to treatment; they gained weight because they ate a high-fat diet. We are also pleased that the treatment reversed the obesity without any of the possible side effects associated with rapid weight loss.

Fat–Tumor Cell Interplay

There has been accelerating interest in “crosstalk” between adipose tissue and tumor cells, promoting growth. Please being us up to speed on this phenomenon.

Obviously, getting rid of extra fat is a good idea because, among other reasons, it reduces the risk of cancer. There is cancer initiation, which is carcinogenesis, and then there is cancer progression, which is growth of the tumor leading to the metastatic stage. Obesity induces inflammation, which is carcinogenic, and also clearly promotes progression of many cancers.

We have identified a definite crosstalk between adipose tissues and the epithelial cell tumors called carcinomas. Such cancers of reproductive and digestive organs (the breast, prostate, and colon) are surrounded by fat tissue. During this interplay between the carcinoma and the fat tissue, there are many cancer-accelerating mechanisms at work. My lab has discovered that stromal cells in fat tissue become mobilized, migrate to the tumor microenvironment, and become a subpopulation of fibroblasts that promote cancer progression to chemotherapy resistance.

Stromal and immune cells from adipose tissue infiltrating carcinomas locally secrete paracrine factors within the tumor microenvironment. Also, mature adipocytes provide adipokines and lipids to cancer cells. We can identify at least three mechanisms involved in the crosstalk between tumor and adipose tissue during cancer progression, but it remains unclear whether obesity has a direct impact on metastatic behavior or is an additional environmental factor.

Looking Ahead

What do you see in the future of this line of research?

There are several new interesting directions of research we are looking into. One is the obesity paradox, whereby some studies have indicated that a higher body mass index actually decreased mortality risk in patients with cancer and helped them respond better to certain therapies, such as immunotherapy. There is growing evidence that when a patient with cancer develops cachexia, excess white fat tissue may be delaying mortality. However, we’re considering the flip-side of the coin, in that excess fat tissue promotes tumor aggressiveness. Once  we better understand the protective aspects of adipose tissue in certain settings, it might provide us with information that could translate into the therapeutic domain.

Another fascinating phenomenon we’re studying is cellular senescence, ie, benign damaged cells that cannot divide but are also resistant to cell death mechanisms. These cells accumulate in adipose tissue and begin secreting toxic cytokines, which contribute to cancer initiation and progression. So, we are looking at certain approaches to rid the adipose tissue of senescent cells, thus preventing one potential line of an inflammatory process that could lead to cancer. 

DISCLOSURE: Dr. Kolonin reported no conflicts of interest.