Overexpression of TGF-β by infiltrated granulocytes correlates with the expression of collagen mRNA in pancreatic cancer

Abstract

Pancreatic cancer is often associated with an intense production of interstitial collagens, known as the desmoplastic reaction. To understand more about desmoplasia in pancreatic cancer, the expression of mRNA for type I and III collagens and potent desmoplastic inducing growth factors transforming growth factor-b (TGF-b), connective tissue growth factor (CTGF), acidic and basic fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) A and C and epidermal growth factor (EGF) was analysed by quantitative RT-PCR. Expression of both collagens in 23 frozen primary pancreatic cancer nodules was significantly higher than that in 15 nonneoplastic pancreatic tissues. The expressions of mRNAs for TGF-b, acidic FGF, basic FGF and PDGF C were likewise higher in surgical cancer nodules, while that of CTGF, PDGF A and EGF were not. Among these growth factors, the expression of TGF-b mRNA showed the most significant correlation with that of collagens (Po0.0001). By immunohistochemistry, TGF-b showed faint cytoplasmic staining in cancer cells. In contrast, isolated cells, mainly located on the invasive front surrounding cancerous nests, were prominently and strongly stained. These TGF-b-positive cells contained a segmented nucleus, were negative for anti-macrophage (CD68) and positive for anti-granulocyte antibodies, indicating their granulocytic nature. In conclusion, TGF-b seemed to play a major role among the various growth factors in characteristic overproduction of collagens in pancreatic cancer. Moreover, the predominant cells that express TGF-b were likely to be infiltrated granulocytes (mostly are neutrophils) and not pancreatic cancer cells.

Evaluation of the prognostic value of systemic inflammation and socioeconomic deprivation in patients with resectable colorectal liver metastases

“…8,9 Neutrophils are the major producers of a number of ligands that may induce tumour cell proliferation and invasion, including transforming growth factor-. 43 Furthermore, granulocytes, particularly neutrophils, contain over two-thirds of circulating vascular endothelial growth factor, liberation of which may promote tumour vascularisation. 44 Neutrophils may further promote invasion and metastasis through the production and release of matrix metalloproteinases 45 and the promotion of cancer cell intra-and extravasation.…”

Extracellular Matrix–Mediated Membrane-Type 1 Matrix Metalloproteinase Expression in Pancreatic Ductal Cells Is Regulated by Transforming Growth Factor-β1

“…Gene expression profiling of tumor-stromal interactions between pancreatic cancer cells and stromal fibroblasts showed that multiple genes are differentially expressed in pancreatic cancer cells and in fibroblasts as a consequence of their mutual interactions (23). Desmoplastic reaction, a very prominent feature of PDACs in vivo (3), is composed of mainly type I collagen deposited by fibroblasts (12), and the extracellular matrix in the desmoplastic reaction has also been shown to modulate the behavior of pancreatic cancer cells (33,35). In this report, we show that the extracellular matrix deposited by pancreatic fibroblasts and cancer cells modulates the behavior of pancreatic ductal cells by inducing a more scattered phenotype and enhancing cell motility.…”

“…Moreover, in human surgical specimens, there is a strong correlation between expression of TGF-h1 mRNA and type I collagen mRNA, suggesting that TGF-h1 may directly be responsible for the fibrotic reaction in PDAC tumors (12). TGF-h1 signals through cell surface serinethreonine kinases to activate cellular responses (13).…”

Neutral endopeptidase inhibits prostate cancer tumorigenesis by reducing FGF-2-mediated angiogenesis

“…The PCR primer pair used for FGF-2 was described previously. 28 Results were obtained as an average of measurements performed in triplicate.…”