Cancer‑associated adipocytes exhibit distinct phenotypes and facilitate tumor progression in pancreatic cancer

Abstract

Adipocyte infiltration in pancreatic cancer (PC) has been demonstrated to be independently associated with PC risk and an active contributor to tumor progression. However, to date, little is known about these unique pancreatic tumor-surrounding adipocytes, or their response to cancer cells. The present study utilized an in vitro indirect coculture model in which the phenotypic changes of adipocytes following exposure to PC cells were directly observed. RNA-sequencing was performed on 3T3-L1 adipocytes cultured with or without Panc-1 cancer cells, and significant changes were identified at the transcriptional level. In terms of delipidation and the impaired function of glucose and lipid metabolism, coculture with tumor cells resulted in an altered metabolic phenotype in mature adipocytes. In co-cultured adipocytes, the appearance of fibroblast-like cells was observed, and the mesenchymal cell differentiation pathway was enriched following the integrated analysis into the transcriptome. In addition, reverse transcription-quantitative PCR analyses of co-cultured adipocytes revealed a loss in gene expression of mature adipocyte markers, and a gain in gene expression of fibroblast-specific markers. It was also confirmed that newly generated cancer-associated adipocytes could facilitate the invasive capacities of the tumor, and may contribute to PC stromal remodeling. The present study supports a novel concept that reprogramming of stromal adipocytes orchestrated by PC cells may generate cancer-associated adipocytes with activated phenotypes, which may ultimately drive pancreatic tumor progression.

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

“…It was proposed that IL-6, released by adipocytes in pro-inflammatory condition, promotes WNT5a expression in PC cell and this in turn mediates phenotypic remodeling of tumor-associated adipocytes [50]. Similar findings were recently reported by another in vitro study, in which morphological and epigenetic signs of mesenchymal differentiation were described in adipocytes co-cultured with Panc-1 and MiaPaCa2 tumor cells [49]. Of note, whole transcriptome analysis of co-cultured adipocytes showed that transcripts modulated by this co-culture were significantly enriched in pathways linked to remodeling of pancreatic TME, such as "cytokine-mediated signaling pathway", "angiogenesis" and "ECM organization" [49].…”

“…Additionally, PC cells may directly stimulate adipocyte lipolysis [25]. Actually, co-culture of pancreatic cancer cells with mature adipocytes caused a reduction of adipose cell size in parallel with an increase of hormone sensitive lipase (HSL) expression In this regard, co-culture of mature adipocytes with Panc-1 and Mia PaCa2 cell determined delipidation, impaired lipid homeostasis and dedifferentiation as the most significant elements for the process of transformation of mature normal adipocytes into CAAs [49]. Indeed, CAAs act as an energy source for tumor cells and contribute to tumor growth by releasing fatty acids (FAs) and glycerol, which represent the main lipid precursor employed for energy purposes by malignant cells (Figure 3) [148].…”

Metabolism of pancreatic cancer: paving the way to better anticancer strategies

“…After coculture with pancreatic cancer cells, adipocytes exhibited smaller size, mesenchymal phenotypes, decreased lipid content and multiple altered metabolic pathways. Such tumor- associated adipocytes could also promote the aggressiveness of pancreatic cancer cells [128]. In addition, a brief study in murine cell lines suggested that pancreatic cancer cells could inhibit Gln degeneration in cocultured adipocytes and then predispose them to Gln secretion.…”

Adipocytes in Breast Cancer, the Thick and the Thin

“…In Vitro Size/TG stores ↑ A size [23] ↓ A size [19] and lipid droplet size [24] ↓ lipid droplets size and number [19,24] ↓ A size and TG content [25] Adipogenesis regulators ↓ C/EBPα and PPARγ [26] -↓ PPARγ and C/EBPα [19,24] ↓ PPARγ and C/EBPα [25,27]…”

“…Glucose transport ↓ GLUT4 [28] -↓ GLUT4 and IRS1 [24] ↓ GLUT4 [32] Lipogenesis ↑ in white AT [33] ↓ (↓HOXC8, HOXC9, FABP4, and HSL) [30] ↓ (↓ FABP4, HSL, ATGL, CIDEA, and FASN) [24] ↓ (↓ SREBP-1c) [32] Lipolytic activity (ATGL/HSL) ↑ in subc. A [34] ↓ HSL [30] ↓ HSL [19] ↑ HSL [35] A: adipocytes; AT: adipose tissue; CAAs: cancer associated adipocytes; subc: subcutaneous; TG: triglycerides.…”