Mini-reviewTumor matrix protein collagen XIα1 in cancer
Introduction
The extracellular matrix (ECM) is an essential component of the cancer cell niche. The ECM is a complex macromolecular network composed of biochemically distinct elements, including polysaccharides, proteoglycans, proteins, and glycoproteins. It provides structural support for cells in the form of the basement membrane, a specialized type of matrix essential for many cellular processes. In addition, the ECM forms the interstitial matrix, which is important in structural tissue support as well as in regulating and integrating cell behavior [1], [2].
The role of the ECM in tumor progression is becoming increasingly clear; a flood of recent research has illustrated that dysregulation of its various components plays an essential role in generating and maintaining the tumor microenvironment [1], [2]. For example, tumor ECM is often stiffer and more highly crosslinked than normal stroma, promoting abnormal cell behavior [3], [4], [5]. Tumor cells are especially sensitive to changes in the stiffness of their environment, specifically increased collagen crosslinking, which then helps to drive the malignant phenotype [3]. A normal, functional ECM is essential for maintaining cellular architecture and polarity, which is universally lost in neoplastic growth. Abnormal ECM also promotes abnormal behavior in stromal cells, including the fibroblasts, immune cells, and endothelial cells that help make up the tumor microenvironment, and thus contributes to the formation and perpetuation of the neoplastic niche [6], [7].
One of the most important components of the ECM, and the most abundant protein in the body, is collagen. Currently there are 28 known collagens, which are trimeric molecules consisting of three polypeptide alpha chains (which may or may not be identical) forming a triple helix structure common to all collagens. The collagen family is diverse, and therefore is divided into three subgroups based on molecular structure and supramolecular assemblies: fibrillar collagens, non-fibril forming collagens, and fibril-associated collagens [8], [9], [10]. Fibrillar collagens are the most abundant, and are capable of forming highly ordered fibrils in the ECM. Fibril-associated collagens, containing interrupted triple helices, associate with and help regulate fibrillar collagens. Non-fibril forming collagens, which include type IV collagen found in the basement membrane, do not form or associate with fibrils [8].
Many previous reports have revealed collagen XI as a player in human disease. Collagen XI is a minor fibrillar collagen most abundantly found in cartilage, but which has also been found in odontoblasts, trabecular bone, skeletal muscle, placenta, lung, and neoepithelium of the brain [11]. Collagen XI copolymerizes with both collagen II and collagen IX, and is essential in maintaining proper fibril diameter and function in connective tissue; absence or mutation in the alpha chain of collagen XI results in abnormally thickened cartilage fibrils [12]. Collagen XI, like all collagens, is a heterotrimer consisting of α1, α2, and α3 chains, located on different chromosomes, which are synthesized as procollagens and proteolytically cleaved to yield mature trimers [11]. The α1 and α2 chains are genetically distinct, while the α3 chain is a hyperglycosylated form of the α1 chain of collagen II. Mutations in the gene encoding the α1 chain of collagen XI (colXIα1) have been implicated in many musculoskeletal disorders, including Stickler syndrome, characterized by ophthalmic, articular, orofacial, and auditory abnormalities [13], [14]; fibrochondrogenesis, a lethal form of dwarfism [15]; as well as osteoarthritis [16], lumbar disc herniation [17], limbus vertebra [18], and Achilles tendinopathy [19].
Recent progress has highlighted an important role for collagen XI in many aspects of neoplastic transformation. This review will focus on the role of collagen XIα1 in cancer.
Section snippets
Dysregulation of collagen XIα1 in cancer
Normal, physiologic expression of collagen XI is very low or nonexistent in most tissues [20], [21], [22]. Therefore, changes in collagen XIα1 (colXIα1) expression associated with cancer are excellent putative markers both of neoplastic change and disease progression.
ColXIα1 was found to be the most highly overexpressed gene in high-stage (versus low-stage) cancer in a meta-analysis of microarray data from multiple cancers [23]. This analysis generated a metastasis-associated gene expression
ColXIα1 and tumor-associated stroma
TAFs are the most abundant cell type within the stroma of many solid malignancies. ColXIα1 was found to be more highly expressed by TAFs isolated from HNSCC explants than in normal fibroblasts derived from cancer-free patients [40]. Immunohistochemical studies in pancreatic cancer have also suggested that colXIα1 may be a marker capable of differentiating TAFs from normal activated fibroblasts, a distinction which has been elusive so far [49]. In ovarian cancer studies, colXIα1 expression was
ColXIα1 as a therapeutic target
Although colXIα1 is clearly active in promoting cancer progression and metastasis, descriptive studies, even with human tissue, are limited in terms of functional or mechanistic significance. Thus it is noteworthy that functional studies in various cancer types have confirmed that dysregulation of colXIα1 expression is indeed playing a relevant role in neoplastic progression (Fig. 1). ColXIα1 siRNA-mediated knockdown in both ovarian cancer cell lines and HNSCC cell lines significantly
Conclusion
The expression pattern of colXIα1 in cancer is obviously complex and incompletely understood. While most studies point to a direct relationship between colXIα1 expression and cancer progression, specifically as it pertains to metastasis, there are some seemingly discordant findings. The expression of colXIα1 changes as the tumor evolves, and differences in study timepoints and the source of the colXIα1, whether it be the tumor itself or the surrounding stroma, may account for large expression
Conflict of interest
None.
Acknowledgement
Department of Otolaryngology, University of Kansas Medical Center and University of Kansas Cancer Center's CCSG (1-P30-CA168524-02) were the funding sources. ZR was supported by the University of Kansas Cancer Center Summer Student Training Grant.
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