Adipocytes as a critical component of the tumor microenvironment.

Obesity increases the risk of incident cancers such as post-menopausal breast, prostate, endometrial, gastrointestinal and renal cancers and is associated with less common hematopoietic malignancies such as leukemia, non-Hodgkin’s lymphoma and multiple myeloma [1]. There has been a growing appreciation of the influence of adipocyte-derived factors on tumor initiation and progression as the primary mediators responsible for increased cancer incidence and mortality. With obesity, there is the overgrowth of white adipose tissue (WAT), affecting insulin resistance, chronic low-grade inflammation and the production of aberrant cytokines and adipokines that are likely to play a role in carcinogenesis [2]. Previously it was thought that adipose tissue served as a potent endocrine organ by secreting adipokines (such as leptin), growth factors (IGF-1, IGFBPs, and TGF-β), pro-inflammatory cytokines (such as TNF-α and interleukin-6) matrix metalloproteinase 11 and stromal cell-derived factor-1 which promote a tumorigenic and pro-invasive microenvironment conducive to metastatic progression [3]. The cytokines and leptin elaborated by the adipocytes and the tumor-associated immune cells and vasculature are likely mediators of poor outcomes in obese cancer patients as they likely contribute to local tumor growth and epithelial–mesenchymal transition. However, signaling by these cytokines and adipokines has remained controversial due to lack of convincing evidence from clinical and animal studies identifying the exact combination of factors driving cancer progression. Pivotal work by Hursting et al. [4] with the fatless mouse showed us that adipose-derived adipokines and growth factors circulating in the blood are not the only survival factors responsible for enhancing tumor growth, migration and invasion. Initially it was believed that only bone marrow-derived cells were recruited to the tumor microenvironment, but adipose stem cells from WAT represent a progenitor population that infiltrate the tumor more often than previously recognized. Using animal models to delineate the role of WAT in cancer progression, Kolonin and colleagues demonstrated in an eloquent series of studies that when transplanted into mice, adipose stromal cells serve as a source of stromal and vascular progenitors to support tumor neovascularization and cell growth giving credence to the paracrine action of adipokines such as leptin acting in the vicinity of the tumor [5]. These studies and others have shown that stromal progenitor cells from endogenous adipose tissue contribute pericytes and adipocytes that populate the tumor microenvironment thereby delivering a self-renewable source of progenitors, cytokines and growth factors important in cancer development, maintenance, chemotherapy resistance and recurrence in solid tumors. Interestingly, the connections between adipocyte derived signals and tumor cell biology have not been limited to solid malignancies. The leptin receptor, expressed on normal hematopoietic stem cells, has also been demonstrated on leukemic cells of both lymphoid and myeloid origin in some patients, positioning the cells to respond to leptin secreted by adipocytes that comprise a significant portion of the bone marrow microenvironment [6]. Consistent with that observation it was noted in a preclinical syngeneic mouse model of acute lymphoblastic leukemia (ALL) utilizing obese mice that the incidence of relapse was notably increased following vincristine therapy. Importantly, this observation was in spite of the drug being dosed proportionally to body weight [7]. Collectively, these observations highlight the need for further investigation of the mechanistic underpinnings of adipose influence on leukemia cell migration, survival, and progression. In the recent study by Pramanik et al. [8] the role of adipose tissue in both the attraction and protection of acute lymphoblastic leukemia cells during chemotherapeutic insult is addressed with an emphasis on the role of the CXCL12 chemokine (stromal cell derived factor; SDF-1α). While CXCL12 has long been recognized as a factor in regulation of both leukemic and healthy hematopoietic progenitor cells in the bone marrow, its role in modulation of tumor burden in adipose tissue highlights the need to better understand its impact and also prompts consideration of adipose tissue as an additional tumor “site of sanctuary” comparable to traditional thought related to the bone marrow microenvironment (where adipocytes are clearly a contributing factor combined with several other stromal elements) and the central nervous system. A mechanistic understanding of the protection of leukemic cells, whether through modulation of local concentrations of chemotherapy, support of tumor cells in a dormant state, or stimulation of overt anti-apoptotic signaling cascades, as discussed by Pramanik’s group, is essential to the development of novel therapeutic strategies to blunt residual disease as an important contributing factor to relapse. This exciting study moves our understanding of the impact of adipose derived cues on ALL disease forward and identifies therapeutic modalities that are currently available, including AMD3100, as options to consider in a novel, clinically relevant context.