Abstract
BackgroundCancer-associated fibroblasts (CAFs) are the most principal cells of depositing and remodeling extracellular matrix (ECM) within solid tumours. Both CAFs and ECM have been demonstrated to play critical roles in tumour development. However, the functional roles of CAFs-associated ECM or ECM remodeling in the pathogenesis of gastric cancer remain unclear.MethodsBioinformatics analysis of the differentially expressed genes between CAFs and corresponding normal fibroblasts (NFs) in gastric cancer was performed. The clinical relevance of hyaluronan and proteoglycan link protein 1 (HAPLN1) was investigated using TCGA data and human gastric cancer specimens. Spheroid cell invasion assay and nude mouse xenograft model were introduced to assay cell invasion. Second harmonic generation (SHG) was used to image and analyze the changes of collagen fibers in ECM.ResultsHAPLN1 was identified as the most significantly up-regulated gene in CAFs of gastric cancer, and higher HAPLN1 levels were associated with shorter overall survival. HAPLN1 was prominently produced by CAFs, and its levels were correlated positively with tumor T staging (P < 0.0001), lymph node metastasis (P = 0.0006) and TNM stage (P = 0.0063). Mechanically, gastric cancer cells activate fibroblasts to up-regulate HAPLN1 expression via activation of TGF-β1/Smad2/3 signaling, which in turn promotes tumour migration and invasion. Importantly, SHG assays with mouse xenograft models and human samples further demonstrated CAFs-derived HAPLN1 increased tumour invasiveness through ECM remodeling.ConclusionsThis study sheds light on the role of CAFs-derived HAPLN1 in the pathogenesis of gastric cancer, and provides insights for the development of novel strategies for prevention and treatment of gastric carcinoma.
Highlights
Gastric cancer remains one of the most common malignancies around the world with more than 1 million estimated new cases annually
Given that hyaluronan and proteoglycan link protein 1 (HAPLN1) is the main extracellular matrix (ECM)-modifying protein [7], we further identified that HAPLN1 is mainly produced by Cancer-associated fibroblasts (CAFs) in human gastric cancer microenvironment, which is associated with the disease progression and poor prognosis
We found that HAPLN1 was the most differentially up-regulated gene in the CAFs compared with that in normal fibroblasts (NFs) (P = 7.81 × 1 0–6) (Fig. 1A, B)
Summary
Gastric cancer remains one of the most common malignancies around the world with more than 1 million estimated new cases annually. Cancer-associated fibroblasts (CAFs) are the most prominent stromal cells in solid tumours including gastric cancer. CAFs act as a key regulator in cancer and exert diverse effects, including extracellular matrix (ECM) deposition and remodeling, extensive reciprocal signaling interactions with cancer cells and crosstalk with infiltrating myeloid cells [2, 3]. Cancer-associated fibroblasts (CAFs) are the most principal cells of depositing and remodeling extracellular matrix (ECM) within solid tumours. Both CAFs and ECM have been demonstrated to play critical roles in tumour development. Gastric cancer cells activate fibroblasts to up-regulate HAPLN1 expression via activation of TGF-β1/Smad2/3 signaling, which in turn promotes tumour migration and invasion. SHG assays with mouse xenograft models and human samples further demonstrated CAFs-derived HAPLN1 increased tumour invasiveness through ECM remodeling. Conclusions This study sheds light on the role of CAFs-derived HAPLN1 in the pathogenesis of gastric cancer, and provides insights for the development of novel strategies for prevention and treatment of gastric carcinoma
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