The role of minor fibril-forming collagens on non-small cell lung cancer progression and metastasis



        Non-small cell lung cancer (NSCLC) represents a common and increasing cause of death in both genders. The main reason for the increased mortality from NSCLC is the inability of its early diagnosis. The NSCLC can be treated surgically in its early stages, and this underlines the need to develop a simple, reliable and cheap molecular marker for the detection of NSCLC in the beginning of carcinogenesis in the lung. The ECM of the lung represent an important constituent and it has been proposed that changes in the ECM of the lung may play a significant role in carcinogenesis. Experimental data have shown that collagen XI alpha-1 is overexpressed in NSCLC and especially in the adenocarcinoma of the lung and the levels of collagen XI alpha-1 have been correlated with the possibility of metastasis.

       The extracellular matrix (ECM) of the lung contains high amounts of various types of collagens and elastin. Collagens type I and III are known as major fibril-forming collagens, they are the most abundant collagens in the ECM of the lung and they are responsible for its tensile strength and elasticity. Under normal conditions collagens type I and III are forming heterotypic fibrils with collagen type V. Collagen type V is characterized as minor fibril-forming collagen, it is expressed in small amounts in the ECM, but plays a critical role in the regulation of the size/diameter of the heterotypic fibrils. Greater proportions of collagen type V have been shown to significantly decrease the diameter of the heterotypic fibrils, and in turn decrease tensile strength; however, other minor fibril-forming collagens may also be involved. One of these collagens is collagen XI alpha-1. Collagen XI alpha-1 is closely related to collagen type V structurally and biologically and previous studies have shown that collagen type XI alpha-1 and collagen type V have the same large globular amino-terminal domain with similar structure and size. It has been described that chains of collagen type XI alpha-1 can be combined with chains of collagen type V forming heteromeric collagen V/XI, especially in tissues other than cartilage. For this reason the minor fibril-forming collagens V and XI have been characterized as a subfamily of collagens, which are expressed in small amounts in the ECM, but they have a crucial role in controlling the size/diameter of heterotypic collagen fibrils. More specifically, the large globular amino-terminal domain has been suggested as a possible mechanism for the reduction of the tensile strength. This reduction occurs through steric hindrance between the large globular amino- terminal domain and the major fibril-forming collagens preventing their assembly into the heterotypic fibrils. Besides this molecular mechanism, which controls the thickness of major fibril-forming collagens, there is also at least one more mechanism, which can act independently or in concert with the mechanism of steric hindrance to control the size/diameter of heterotypic fibrils. Detailed proteomic analysis of the large globular amino-terminal domains of collagen type V and XI alpha-1 has shown that these domains contain a well-characterized heparine binding domain (HBD). It is also known from other studies that the HBD can interact with various receptors in the ECM. For example an increased synthesis and activation of matrix metalloproteases can be occurred through the activation of integrin receptors alpha-4 beta-1 from HBD, which in turn can lead to increased degradation of the ECM.



 Aim of the study

           In the present study we plan to determine the gene expression differences, at both the mRNA and protein level, of all fibril-forming collagens and their specific integrin receptors in surgical specimens from patients with NSCLC and to compare these results with normal lung. In addition, we plan to detect and correlate any changes at the mRNA level of fibril-forming collagens in the corresponding patients’ peripheral blood. The quantification of these macromolecules may represent novel biomarkers for the detection of the stage of this type of cancer, as well as for prognosis determination.