TGF-β Pathway Activity in Pancreatic Versus Biliary Tract Cancers

Special Article - Pancreatic cancer Surgery

Austin J Surg. 2018; 5(1): 1119.

TGF-β Pathway Activity in Pancreatic Versus Biliary Tract Cancers

Aghamaliyev U1#, Rech A1*#, Hablawetz P1, Kiesslich T3, Gaiser T4, Thomas M5, Breitkopf- Heinlein K6 and Rückert F1

¹Department of Surgery, University Medicine Mannheim and Heidelberg, Germany

²Department of Internal Medicine I, Paracelsus Medical University, Austria

³Laboratory for Tumor Biology and Experimental Therapies (TREAT), Institute of Physiology and Pathophysiology, Paracelsus Medical University, Austria

4Department of Pathology, University Medicine Mannheim and Heidelberg, Germany

5Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Germany

6Department of Internal Medicin II, University Medicine Mannheim and Heidelberg, Germany #These authors have contributed equally to this study

*Corresponding author: Andrea Rech, Department of Surgery, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, University of Heidelberg, Germany

Received: November 20, 2017; Accepted: January 03, 2018; Published: January 10, 2018


Background and Aims: It has been observed that pancreato-biliary cancers go along with a prominent desmoplastic reaction, which seems to play a crucial role in migration and metastasis. Transforming Growth Factor β (TGF-β) is a key-player in tumor progression and metastasis contributes to this desmoplastic reaction. The histological characteristics of the desmoplastic reaction in Cholangio Cellular Carcinoma (CCC) seem to be comparable to those in Pancreatic Ductal Adeno Carcinoma (PDAC). The aim of the present study therefore was to analyze differences in TGF-β signaling between PDAC and CCC.

Material and Methods: Established cell lines of CCC and PDAC were analyzed for expression of each of the 27 TGF-β pathway signaling genes using the Fluidigm’s Biomark high-throughput qPCR chip platform. Eighteen PDAC and ten CCC cell lines served as samples. Furthermore, to validate the findings we either performed Western Blotting or immune histochemistry of Activin Receptor-Like Kinase 1 (Alk1) and Thrombospondin 1 (TSP-1).

Results: The Fluidigm microfluidics dynamic array showed a significantly lower expression of Alk1 (0.00-7.39 95% C.I.; p=0.004) in CCC cell lines when compared to PDAC cell lines. In contrast, the expression of TSP-1 (5,8 E+152; 3,307 - 4,76 E+170 95% C.I.; p=0.004) and Cyclin D1 (3.008; 0.394-26.330 95% CI; p=0.004) was significantly up regulated in CCC cell lines. However, these findings could neither be confirmed by Western Blotting nor by immune histochemistry.

Discussion: The majority of the identified members of the canonical TGF-β pathway seemed to be expressed homogenously in CCC and PDAC cell lines. Alk1 and TSP-1 had a distinct differential expression in CCC cell lines in The Fluidigm microfluidics dynamic array. A reason for a lack of confirmation by other methods could be the complexicity of mRNA and protein expression of the TGF-β pathway and the influence of cell-cell interactions in the in vivo situation, e.g., via inflammatory stroma reaction.

Keywords: Pancreato-biliary cancers; Pancreatic cancer; Cholangiocellular cancer; TGF-beta pathway; Thrombospondin-1; Desmoplastic reaction


Pancreato-biliary cancers are aggressive gastrointestinal malignancies, characterized by a poor prognosis [1]. These cancer types have been observed to have a prominent desmoplastic reaction [2,3]. Profound evidence suggests, that the desmoplastic reaction leads to a poorly perfused and poorly vascularized tissue. As an effect, delivery and efficacy of chemotherapeutics is limited [2]. It has been further reported that interaction between cancer cells and their surrounding microenvironment might play a crucial role in migration and metastasis formation in these cancers [4]. The desmoplastic reaction therefore seems to play a role in important clinical characteristics of the tumors.

Histopathologic analyses of the desmoplastic reaction in pancreato-biliary cancers is characterized by an abundant extracellular matrix, fibroblasts, stellate cells, immune cells, nerve cells, growth factors and cytokines. The desmoplastic reaction is associated with an abnormal vasculature with numerous circuitous small leaky blood vessels and capillaries [4,5] (Figure 1). The extracellular matrix itself is composed of a variety of fibrous proteins, glycoproteins, proteinases and glycosaminoglycans as well as modulators of the cell-matrix interaction such as periostin, tenascin C, SPARC and Thrombospondin 1 (TSP-1) [6-9].