Cancer-associated fibroblasts promote progression and gemcitabine resistance via the SDF-1/SATB-1 pathway in pancreatic cancer

Shangyou Zheng,Lusheng Wei,Rufu Chen,Yuanting Lu,Quanbo Zhou,Qing Lin,Yimin Liu,Zhihua Li,Guolin Li,Huilin Ye

doi:10.1038/s41419-018-1104-x

Shangyou Zheng, Lusheng Wei + Show 8 more

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https://doi.org/10.1038/s41419-018-1104-x

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Abstract

Cancer-associated fibroblasts (CAFs), a dominant component of the pancreatic tumor microenvironment, are mainly considered as promotors of malignant progression, but the underlying molecular mechanism remains unclear. Here, we show that SDF-1 secreted by CAFs stimulates malignant progression and gemcitabine resistance in pancreatic cancer, partially owing to paracrine induction of SATB-1 in pancreatic cancer cells. CAF-secreted SDF-1 upregulated the expression of SATB-1 in pancreatic cancer cells, which contributed to the maintenance of CAF properties, forming a reciprocal feedback loop. SATB-1 was verified to be overexpressed in human pancreatic cancer tissues and cell lines by quantitative real-time PCR, western blot, and immunohistochemical staining, which correlated with tumor progression and clinical prognosis in pancreatic cancer patients. We found that SATB-1 knockdown inhibited proliferation, migration, and invasion in SW1990 and PANC-1 cells in vitro, whereas overexpression of SATB-1 in Capan-2 and BxPC-3 cells had the opposite effect. Immunofluorescence staining showed that conditioned medium from SW1990 cells expressing SATB-1 maintained the local supportive function of CAFs. Furthermore, downregulation of SATB-1 inhibited tumor growth in mouse xenograft models. In addition, we found that overexpression of SATB-1 in pancreatic cancer cells participated in the process of gemcitabine resistance. Finally, we investigated the clinical correlations between SDF-1 and SATB-1 in human pancreatic cancer specimens. In summary, these findings demonstrated that the SDF-1/CXCR4/SATB-1 axis may be a potential new target of clinical interventions for pancreatic cancer patients.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and aggressive solid malignancies, with a dismal 5-year survival rate of < 7%1
Characterization of primary NAFs and Cancer-associated fibroblasts (CAFs) The human pancreatic normal tissue-associated fibroblasts (NAFs) and CAFs were isolated from fresh pancreatic cancer tissue and adjacent non-neoplastic pancreatic tissue, further confirmed with postoperative cancer tissue by immunohistochemistry staining of αSMA (Fig. 1a)
We demonstrated that SDF-1, known as C-X-C motif chemokine 12 (CXCL12), secreted by CAFs upregulated SATB-1 expression in pancreatic cancer cells via the SDF1/CXCR4 axis

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and aggressive solid malignancies, with a dismal 5-year survival rate of < 7%1. The absence of early symptoms and aggressive biological characteristics of tumor are among the reasons for late detection, which makes PDAC act as a silent killer with only 15–20% of cases diagnosed in the early resectable stages[3]. In most patients (74%), receiving gemcitabine tumor recurrence is eventually observed, with only 13.4 months of disease-free survival[4]. Official journal of the Cell Death Differentiation Association. Wei et al Cell Death and Disease (2018)9:1065 behavior and intricate cellular communication is the prerequisite to developing effective therapeutic strategies. PDAC is characterized as an abundant desmoplastic tissue that accounts for up to 80% of total tumor mass[5]

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