Paracrine and endocrine effects of adipose tissue on cancer development and progression

Abstract

The past few years have provided substantial evidence for the vital role of the local tumor microenvironment for various aspects of tumor progression. With obesity and its pathophysiological sequelae still on the rise, the adipocyte is increasingly moving center stage in the context of tumor stroma-related studies. To date, we have limited insight into how the systemic metabolic changes associated with obesity and the concomitant modification of the paracrine and endocrine panel of stromal adipocyte-derived secretory products ("adipokines") influence the incidence and progression of obesity-related cancers. Here, we discuss the role of adipocyte dysfunction associated with obesity and its potential impact on cancer biology.

Fig. 1.

Paracrine and endocrine interactions of adipocytes with cancer cells. A, Paracrine signals (tumor microenvironment). Both cell-autonomous signals and paracrine signals derived from stromal cells control tumor cell physiology. The tumor microenvironment contains a number of cell types, including adipocytes, fibroblasts, immune cells, tumor-associated macrophages (TAMs), and myoendothelial cells, all of which mediate paracrine signaling in the microenvironment. Adipocytes constitute a key stromal cell type and interact with cancer cells by secreting a variety of signaling molecules that include ECM constituents, adipokines, inflammatory cytokines, and angiogenic factors. HGF, Hepatocyte growth factor. B, Endocrine signals (systemic effects). During the process of adipocyte hypertrophy and hyperplasia associated with the obese state, adipose tissues become dysfunctional due to metabolically challenging conditions, such as hypoxia and oxidative and ER stress. The metabolic consequences of adipose tissue dysfunction, such as adipokine dysregulation, chronic inflammation, dyslipidemia, and hormonal dysregulation, result in insulin resistance. As a result, adipose tissue not only affects proximal tumor cells but also influences distal tumor cell behavior through altered expression of cytokines, insulin, and adipokines.

Fig. 2.

Crosstalk among the signaling pathways linking obesity and breast cancer progression. The EGFR (epidermal growth factor receptor) family, such as EGFR (ErbB1), and ErbB2/HER2/Neu, plays an important role in tumorigenesis by inducing cells to proliferate and to survive. Upon ligand binding to EGFR, downstream pathways including kinases such as PI3K, ERK, and JAK/STAT are activated in a coordinated manner to promote cell proliferation and survival. The estrogen receptor ERα triggers EGFR pathways, which are also directly regulated by adipokines, such as adiponectin and leptin through their receptors AdipoR1, AdipoR2, and LEPR-B, respectively, which are expressed in mammary tumor cells. Importantly, adiponectin and leptin modulate estrogen (ER) production through regulation of aromatase activity in adipose tissue, resulting in altering ERα and EGFR pathways in cancer cells. LEPR-B mediated downstream signaling, such as PI3K, ERK and JAK/STAT3 is well-known to be involved in protumorigenic pathways. Adiponectin actions are multifaceted. Activation of ceramidase activity through AdipoR1 and AdipoR2 causes proangiogenic and antiapoptotic responses. Ceramide inhibits Akt pathways, whereas S1P activates antiapoptotic pathways. Inflammatory cytokines, such as TNFα and IL-6, and ECMs secreted from adipose tissue also contribute to cancer progression through their receptors. These include RTKs (receptor-tyrosine kinases) and integrin-mediated pathways. Downstream mediators, such as NF-κB and focal adhesion kinase (FAK) convey the EGFR signal to the nucleus and also affect other adipokine-stimulated downstream pathways. High insulin levels frequently observed in obese subjects augment promitogenic insulin/IGF-I signaling. Proangiogenic factors, such as vascular endothelial growth factor (VEGF) secreted from adipose tissue, contribute to angiogenic capacities of endothelial cells within the tumor microenvironment. Adiponectin receptors and T-cadherin expressed in tumor endothelial cells may be associated with angiogenesis. Therefore, various signaling pathways triggered by adipokines converge upon oncogenic signaling pathways in mammary tumor cells to promote tumor progression.

Fig. 3.

Potential involvement of adipocytes in tumor progression. Metabolically healthy adipocytes are crucial to maintaining whole body energy metabolism. Obesity-induced dysregulation of adipocytes can be associated with tumor progression. Contributing factors include: 1) hypoxia due to inadequate expansion of adipocytes in obesity; 2) fibrosis, which is associated with dedifferentiation of stromal adipocytes into fibrogenic preadipocytes during the EMT process within the tumor microenvironment. Drastic remodeling of the extracellular matrix by dysfunctional adipocytes contributes to enhanced fibrosis; 3) increased adipocyte apoptosis/necrosis triggers macrophage infiltration into adipose tissues and obesity-dependent chronic inflammation; and 4) disturbance of local hormonal milieu. These changes promote a more “tumor-friendly” environment through dysregulation of adipokines and chemokines as well as hormones and lipid metabolites.

Fig. 4.

Pharmacological options for modulating adipose tissue-associated hormonal and metabolic effects. Stromal preadipocytes of adipose tissue, which are derived from mesenchymal stem cells or EMT, are a major source of aromatase activity. To modulate hormonal effects of adipose tissues, two different approaches have been entertained: 1) induction of preadipocyte differentiation to healthy adipocytes; and 2) inhibition of aromatase activity. A variety of pharmacological agents are available to induce preadipocyte differentiation. Most agents that induce preadipocyte differentiation do so through PPARγ-dependent mechanisms. This results in increased adiponectin levels, reduced inflammation, and improved insulin sensitivity. Steroidal (type I) and nonsteroidal (type II) aromatase inhibitors and NSAID have been widely used to inhibit aromatase activity. From a metabolism perspective, systemic metabolic abnormalities due to dysfunctional adipocytes in obesity are key risk factors of tumor progression. Agents that normalize metabolic abnormalities, such as insulin resistance, chronic inflammation, and adipokine dysregulation, are potentially useful to treat obesity-related cancers. In this regard, PPARγ agonists and metformin, both widely used agents in the diabetes clinic, are under investigation. CRP, C-reactive protein.