Fueling the Tumor Microenvironment with Cancer-Associated Adipocytes Free

It was as recent as the early 2000s that the tumor microenvironment (TME) began to be widely appreciated as an important contributing factor to tumor progression. At that time, most studies on the TME were focused on the role of fibroblasts and extracelluar matrix components, angiogenesis and inflammation. The hypothesis that adipocytes may too play a role in tumor progression was proposed in the 1960s by Spector; however, it was not until decades later that Iyengar and colleagues demonstrated that adipocytes promote tumor progression via the secretion of soluble factors (1). This important finding paved the way for the work of Dirat and colleagues, which led to the discovery of cancer-associated adipocytes (CAA) and their influence on local invasion of breast cancer (Fig. 1; ref. 2).

Adipocytes are abundant in the breast TME where they often interact with cancer cells, yet these cells were largely dismissed as innocent bystanders in early TME research. In their landmark study, Dirat and colleagues characterized the phenotypic and functional changes of adipocytes resulting from direct contact with breast tumor cells (2). Using in vitro differentiated murine preadipocytes (F442A) cocultured with mammary tumor cells, they demonstrated the delipidation of adipocytes in contact with tumor cells—a phenotypic change confirmed with histologic analysis of human mammary tumors. Under coculture conditions with mature adipocytes, tumor cells showed increased growth and invasion capabilities. Moreover, tumor cell-adipocyte cocultures dramatically reduced the expression of adipocyte differentiation markers such as hormone-sensitive lipase (HSL), resistin, and adiponectin, coinciding with increased expression of proteases and proinflammatory cytokines (e.g., IL6, IL1β, TNFα) and matrix remodeling proteins (e.g., MMP-11, PAI-1). As a result of these important discoveries, the term “CAA” was coined to designate adipocytes with this unique tumor-induced activation state (2). Subsequent work by the same team demonstrated that over time, persistent contact between adipocytes and tumor cells caused them to acquire a spindle-like morphology and become “adipocyte-derived fibroblasts” (ADF; ref. 3), constituents of the cancer-associated fibroblast population within the tumor (commonly known as “CAF”). It was initially shown that ADFs stimulate increased migratory capacity of breast cancer cells (3), but these effects have since been confirmed in a wide variety of cancer types, such as melanoma, prostate, colon, and ovarian cancers. Indeed, it is now appreciated that, in many solid tumors, the invasion of tumor cells into the proximal adipose tissue leads to profound delipidation and activation of adipocytes.

Among the most clinically significant findings by Dirat and colleagues was the discovery that CAA-produced IL6 was functionally responsible for bolstering the invasive capacity of tumor cells (2), This inflammatory state of CAAs resembles that found in adipose tissue under obese conditions, and reflects the clinical characteristics of breast tumors in obese women with more locally advanced disease. It may also partially explain the link between obesity and enhanced breast cancer mortality, as invasion is a hallmark requirement for metastatic dissemination. The discovery of CAAs has thus facilitated our understanding of the link between obesity and breast cancer progression, where adipocytes are central to host physiology.

The discoveries from Dirat and colleagues opened many new questions in the TME field related to adipocytes and their interplay with tumor cells (2). Notably, a key emerging concept was related to the liberation of free fatty acids (FFA) from adipocytes through lipolysis, which could act as a fuel source for cancer through mitochondrial fatty acid oxidation (FAO)—an observation first described by Nieman and colleagues in omental metastasis of ovarian cancer (4). Importantly, the communication between tumor cells and peritumoral adipocytes was bidirectionally regulated (Fig. 1); tumors actively promoted adipocyte lipolysis to stimulate the release of FFAs, which were then recaptured as an energy substrate (4). Consistent with this finding, the transfer of FFAs from adipocytes to tumor cells under coculture conditions was later confirmed in breast cancer (5, 6), which promoted FAO and functionally supported tumor cell proliferation, migration, and invasion (5, 6). FFA transfer was further exascerbated in the presence of lipid-loaded adipocytes (a model used to mimic obesity), which boosted the proliferative and migratory effects, again supporting the notion that obesity may enhance CAA-mediated effects within the TME (6).

FFA released by CAA can be stored in tumor cells within lipid droplets, which can in turn be released into the microenvironment over time via an adipose triglyceride lipase (ATGL)-dependent lipolytic pathway (5). Wang and colleagues demonstrated that ATGL is detected in human mammary tumors in association with tumor aggressiveness and invasion, and its expression in tumor cells is increased upon contact with adipocytes (5). This proinvasive effect of adipocytes can be mitigated via inhibition of ATGL-dependent lipolysis or FAO pathways (5), highlighting their potential value as therapeutic targets to combat breast cancer progression. Besides the direct transfer of FFAs, CAAs secrete exosomes rich in proteins involved in FAO, responsible for metabolic remodeling of tumor cells to promote their progression (7). These exosomes become more numerous in conditions of obesity, increasing the metabolic symbiosis between adipocytes and tumor cells with an increase in FFAs present in exosomes released by CAAs (8). Communication through adipocyte-derived extracellular vesicles has since been observed in many tumor types, such as breast, pancreatic, colorectal, melanoma, and stomach cancer.

Beyond their metabolic interplay, CAAs and breast tumor cells communicate via secreted cytokines and chemokines within the TME. In addition to IL6 that was highlighted by Dirat and colleagues, various studies have shown that CAAs can also secrete high levels of CCL2, CCL5, IL1β, TNFα, VEGF, and leptin, which similarly cause increased proliferation and invasion of tumor cells and angiogenesis. Moreover, these cytokines can promote the infiltration of immune cells to orchestrate extensive inflammatory changes within the TME, which is amplified under conditions of obesity where death of the adipocytes themselves triggers substantial innate immune responses. For example, in obesity-associated pancreatic cancer, adipocyte hypertrophy and hyperplasia coincides with their production of IL1β, which promotes the infiltration of neutrophils that act on pancreatic stellate cells to exascerbate desmoplasia (9). Ultimately, these effects lead to cancer progression and chemotherapy resistance (9). Similar mechanisms of CAA–immune cross-talk are known to be relevant to other tumor types that are sensitive to obesity and display TMEs rich in adipocytes, including breast, prostate, and ovarian cancer, as well as metastatic tumors that respond to the systemic effects of the adipose tissue microenvironment.

Finally, complementing the ability of CAAs to shape tumors via lipids or cytokines, the generation of reactive oxygen species (ROS) also plays an important role. In prostate cancer models, Laurent and colleagues showed that the bidirectional dialog between tumor cells and CAAs within the periprostatic adipose tissue increases the invasive capacity of tumor cells (10). Mechanistically, NOX5 expression was increased in prostate cancer cells following lipid uptake, resulting in the generation of intracellular ROS and subsequent activation of the HIF1/MMP14 pathway to promote invasion—a process increased in conditions of obesity (10). How obesity-associated adipose tissue influences ROS production in other cells within the microenvironment, including immune cells, is an area of active investigation and may be influenced by tumor cell–CAA interactions.

Ultimately, the discovery and characterization of CAA biology by Dirat and colleagues (2) unveiled the inflammatory potential of peritumoral adipocytes and led to a new area of research aimed at understanding the metabolic mechanisms linking obesity and poor prognosis in breast cancer. This shift in thinking about adipocytes as active players within the TME—not mere innocent bystanders—has paved the way for further research to identify potential therapeutic targets. The next step in the field will be to translate some of these fundamental discoveries to the clinic, particularly in the context of obesity-associated breast cancer, where it is likely to have the most meaningful impact on disease biology and patient outcomes.

No disclosures were reported.