Cells lines vs. animals studies for developing new therapeutic strategies in human pancreatic cancer?

In the past, most of the knowledge gained regarding the physiology and the pathology of the pancreas has been evaluated in experimental studies on animals especially on rats/mice. This approach has been criticized in recent years because most of the data obtained from animals cannot be fully applied to humans [1]. A new approach to the physiology and pathology of the pancreas comes from studying its molecular biology, and the results obtained seem to be more reliable than those obtained in animals. An example of this assumption comes from studies on pancreatic ductal adenocarcinoma: this cancer seems to result from a progressive accumulation of mutations in genes such as K-ras, CDKN2A, p53, BRCA2, p164ink, and SMAD4 [2]; in particular, the SMAD4 mutations which result in the constitutive activation of transforming growth factor b1 signalling, are generally considered to be responsible for the desmoplastic response, which includes upregulated expression of the extracellular matrix, and type I collagen [3, 4, 5, 6]. Grzesiak et al. [7, 8] have also shown that a2b1 integrin-mediated adhesion on type I collagen promotes a malignant phenotype in FG pancreatic cells, as defined by increased proliferation and haptokinetic cell migration, downregulated expression and localization of E-cadherin and b-catenin in cell-cell contacts, increased phosphorylation of GSK3b and PKB/Akt, and downregulated expression of PTHrP, IL-6, and IL-8 as compared to fibronectin, type IV collagen, laminin, or vitronectin. These results are in agreement with previous studies demonstrating that type I collagen downregulates E-cadherin expression in Panc-1, BxPC-3, and PaTu8988s pancreatic cancer cells, resulting in increased proliferation and migration compared to fibronectin. Recently, the same group of researchers demonstrated similar phenotypic differences in BxPC-3, Colo-357, and CFPAC cells on type I collagen as compared to fibronectin; that is, increased haptokinetic cell migration, downregulated expression and localisation of E-cadherin and b-catenin in d isrupted cell-cell contacts, increased phosphorylation of GSK3 and PKB/Akt, and decreased expression of PTHrP, IL-6, and IL-8. Furthermore, functional studies with pharmacological inhibitors for GSK3 and PKB/Akt suggest that these signalling effectors are involved in the mechanism of a2b1 integrin-mediated regulation of the malignant phenotype in FG cells. Type I collagen, in particular, seems to play an active role in vitro and in vivo in the pathophysiology of pancreatic cancer [9, 10] as demonstrated by in vitro studies which have shown how pancreatic cancer cell lines stimulate the production of type I collagen from adjacent stellate cells, which resulted …