The Role of Dysfunctional Adipose Tissue in Pancreatic Cancer: A Molecular Perspective

Abstract

Pancreatic cancer (PC) is a lethal malignancy with rising incidence and limited therapeutic options. Obesity is a well-established risk factor for PC development. Moreover, it negatively affects outcome in PC patients. Excessive fat accumulation in obese, over- and normal-weight individuals induces metabolic and inflammatory changes of adipose tissue microenvironment leading to a dysfunctional adipose "organ". This may drive the association between abnormal fat accumulation and pancreatic cancer. In this review, we describe several molecular mechanisms that underpin this association at both local and systemic levels. We focus on the role of adipose tissue-derived circulating factors including adipokines, hormones and pro-inflammatory cytokines, as well as on the impact of the local adipose tissue in promoting PC. A discussion on potential therapeutic interventions, interfering with pro-tumorigenic effects of dysfunctional adipose tissue in PC, is included. Considering the raise of global obesity, research efforts to uncover the molecular basis of the relationship between pancreatic cancer and adipose tissue dysfunction may provide novel insights for the prevention of this deadly disease. In addition, these efforts may uncover novel targets for personalized interventional strategies aimed at improving the currently unsatisfactory PC therapeutic options.

Keywords: adipose tissue; obesity; pancreatic cancer.

Figure 1

Systemic mediators of dysfunctional adipose tissue effects on pancreatic cancer cell. Excess fat accumulation induces hypoxia and low-grade inflammation in the adipose tissue, resulting in altered secretion of pro-inflammatory cytokines and adipokines. Increased release of TNF-α, Interleukin-1β (IL-1 β) and IL-6 stimulate pancreatic cancer (PC) cell proliferation via activation of the NF-kB, MAPK/ERK and JNK signaling pathways. Elevated circulating leptin may drive pancreatic tumor invasion and metastasis triggering the JAK2/STAT3 axis. Other adipokines, including resistin, lipocalin-2, apelin and visfatin, may also promote PC growth and progression. Reduced release of adiponectin by dysfunctional adipocytes decreases tumor-suppressor effects of adiponectin, mediated by JAK2/STAT3 inhibition and down-regulation of intracellular β-catenin. Expansion and inflammation of visceral adipose tissue induce insulin resistance that fosters systemic secretion of insulin and IGF-1. Activation of insulin receptor (IR) and insulin-like growth factor-I receptor (IGF-IR) enhances PC proliferation through the PI3K/mTOR and MAPK/ERK pathways.

Figure 2

Overview of interactions between gut microbiota, adipose tissue and pancreatic cancer development. High fat diet (HFD)-induced gut dysbiosis promotes systemic lipopolysaccharide (LPS) release and subsequent activation of TRL4 receptor in adipose tissue macrophages. Resulting adipose tissue inflammation contributes to PC development (blue lines). HFD-promoted adipose tissue inflammation favors periodontal inflammation and oral colonization by pathogen bacteria that are related with increased risk of PC (green lines). Gastric colonization by Helicobacter pylori fosters HFD-mediated central obesity and insulin resistance, both of which promote PC growth. PC may also be favored by direct translocation of Helicobacter pylori-derived protein antigen toward pancreatic tissue and subsequent pancreatic inflammation (orange lines).

Figure 3

Crosstalk between local adipose tissue and pancreatic cancer. Pancreatic tumor cells stimulate adipocyte dedifferentiation and lipolysis, thus promoting transformation of local adipocytes into cancer associated adipocytes (CAAs). Delipidation and impaired metabolic homeostasis of CAAs are associated with increased release of fatty acids (FAs), glycerol and glutamine, which are used as energy source for cancer cell growth. Increased expression of MMP11 and collagen I, secondary to acquired fibroblast-like properties of CAAs, promotes extracellular matrix (ECM) remodeling within tumor microenvironment (TME), favoring PC invasiveness and metastasis.