Cancer-associated adipocytes promote pancreatic cancer progression through SAA1 expression.

Abstract

Although pancreatic cancer often invades peripancreatic adipose tissue, little information is known about cancer-adipocyte interaction. We first investigated the ability of adipocytes to de-differentiate to cancer-associated adipocytes (CAAs) by co-culturing with pancreatic cancer cells. We then examined the effects of CAA-conditioned medium (CAA-CM) on the malignant characteristics of cancer cells, the mechanism underlying those effects, and their clinical relevance in pancreatic cancer. When 3T3-L1 adipocytes were co-cultured with pancreatic cancer cells (PANC-1) using the Transwell system, adipocytes lost their lipid droplets and changed morphologically to fibroblast-like cells (CAA). Adipocyte-specific marker mRNA levels significantly decreased but those of fibroblast-specific markers appeared, characteristic findings of CAA, as revealed by real-time PCR. When PANC-1 cells were cultured with CAA-CM, significantly higher migration/invasion capability, chemoresistance, and epithelial-mesenchymal transition (EMT) properties were observed compared with control cells. To investigate the mechanism underlying these effects, we performed microarray analysis of PANC-1 cells cultured with CAA-CM and found a 78.5-fold higher expression of SAA1 compared with control cells. When the SAA1 gene in PANC-1 cells was knocked down with SAA1 siRNA, migration/invasion capability, chemoresistance, and EMT properties were significantly attenuated compared with control cells. Immunohistochemical analysis on human pancreatic cancer tissues revealed positive SAA1 expression in 46/61 (75.4%). Overall survival in the SAA1-positive group was significantly shorter than in the SAA1-negative group (P = .013). In conclusion, we demonstrated that pancreatic cancer cells induced de-differentiation in adipocytes toward CAA, and that CAA promoted malignant characteristics of pancreatic cancer via SAA1 expression, suggesting that SAA1 is a novel therapeutic target in pancreatic cancer.

• Authors: Masanori Takehara, Yasushi Sato, Tetsuo Kimura, Kazuyoshi Noda, Hiroshi Miyamoto, Yasuteru Fujino, Jinsei Miyoshi, Fumika Nakamura, Hironori Wada, Yoshimi Bando, Tetsuya Ikemoto, Mitsuo Shimada, Naoki Muguruma, Tetsuji Takayama
• Journal: Cancer science (Cancer Sci) Vol. 111 Issue 8 Pg. 2883-2894 (Aug 2020) ISSN: 1349-7006 [Electronic] England
• PMID: 32535957 (Publication Type: Journal Article)
• Copyright: © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Culture Media, Conditioned
• RNA, Small Interfering
• SAA1 protein, human
• Serum Amyloid A Protein

Topics

• 3T3 Cells
• Adipocytes (pathology)
• Adult
• Aged
• Aged, 80 and over
• Animals
• Cell Dedifferentiation
• Cell Line, Tumor
• Cell Proliferation
• Coculture Techniques
• Culture Media, Conditioned (metabolism)
• Disease Progression
• Disease-Free Survival
• Epithelial-Mesenchymal Transition
• Female
• Follow-Up Studies
• Gene Knockdown Techniques
• Humans
• Male
• Mice
• Middle Aged
• Pancreas (pathology, surgery)
• Pancreatectomy
• Pancreatic Neoplasms (mortality, pathology, surgery)
• Prognosis
• RNA, Small Interfering (metabolism)
• Retrospective Studies
• Serum Amyloid A Protein (genetics, metabolism)