|Ahead of print publication
Deciphering the “Collagen code” in tumor progression
Archana Anshuman Gupta1, Supriya Kheur2, Sangeeta J Palaskar1, Bindiya R Narang1
1 Department of Oral Pathology and Microbiology, Sinhgad Dental College and Hospital, Pune, Maharashtra, India
2 Department of Oral Pathology and Microbiology, Dr. DY Patil Vidyapeeth, Pune, Maharashtra, India
Archana Anshuman Gupta,
Department of Oral Pathology and Microbiology, Sinhgad Dental College and Hospital, S. No. 44/1, Vadgaon Budruk, Off Sinhgad Road, Pune - 411 041, Maharashtra
Source of Support: None, Conflict of Interest: None
Invasion and metastasis are the fundamental properties of tumor biology and the root causes of cancer death. With the elucidation of genetic and epigenetic mechanisms, it has been postulated that cancer is a disease of imbalance. It is not merely a disease of tumor cells but also the body's mismanagement of those tumor cells. Tumor microenvironment plays an important role in tumor progression via the co-evolution of tumor cells and tumor stroma. Hence, exploring the complex mechanisms of tumor progression from perspectives of tumor stroma has become a new frontier. The major component of tumor stroma, the extracellular matrix (ECM), acts as a key regulator of cell and tissue function. Conventionally, the role of ECM was considered primarily as a physical scaffold that binds cells and tissues together. However, recent studies revealed the biochemical and biophysical signaling properties of the ECM as well that affect cell adhesion and migration, tissue morphogenesis and repair, and angiogenesis and cancer. The most abundant constituent of ECM, collagen, accounts for the major function of ECM, which can be associated with increased malignancy. The present review summarizes the dynamic interplay between collagen and tumor cells. It focuses on changes in physicochemical-biological properties of collagen. A new paradigm has been formulated that collagen can no more be considered playing a passive role over which tumor progression and metastasis takes place. Rather, its active role in the promotion of tumor progression and metastasis should be explored.
Keywords: Collagen, extracellular matrix, oral squamous cell carcinoma, tumor microenvironment
| > Introduction|| |
Cell–extracellular matrix (ECM) adhesion is a fundamental process through which cells interact and communicate with the environment. Tissue-specific functions are achieved by interactions between the cell and its surrounding ECM, as postulated by Bissell et al. in 1982. According to this model, there is a dynamic bidirectional cross talk between the ECM and the cell membrane which is extended to the broad realm of gene expression in the cell nucleus and henceforth back again. Through this model, ECM has been viewed as an integral determinant of tissue specificity along with the cellular microenvironment which includes adhesive and soluble paracrine signals from the neighboring cells and distant tissues. One of the central themes in classical embryology, the concept of local microenvironments, or niches, playing an important role in regulating cell behavior, has now become increasingly accepted in cancer biology too. Much effort has already been devoted in determining how cellular components of the niche initiate and promote cancer development. However, recent progress in the field also highlighted the abnormal ECM dynamics in terms of excess ECM production or reduced ECM turnover as one of the most ostensible clinical outcomes in diseases such as tissue fibrosis and cancer.
The main contributors of altered activities of ECM remodeling enzymes and thus abnormal ECM metabolism are stromal cells, including cancer-associated fibroblasts and immune cells. Like many other ECM components and their receptors such as heparan sulfate, proteoglycans and CD44 that facilitate growth factor signaling are Frequently overproduced in cancer, various collagens, including Collagens I, II, III, V, and IX, also show increased deposition during tumor formation. And as we age, there is a reduction of collagen deposition and increased matrix metalloproteinase (MMP) activity.
The main challenge in the treatment of oral squamous cell carcinoma (OSCC) is its highly invasive nature and to be invasive, a tumor cell must be able to penetrate and move through the stroma. Specific interactions with tumor cell–surface adhesion receptors and multiple adhesive components of the ECM are involved in the tumor dissemination process.
This short communication is an attempt to throw light on a new paradigm that collagen being the most important architecture of ECM upon which metastasis takes place, it cannot be considered as just a passive player during tumor progression.
| > Collagen in Health|| |
Collagen is abundant in humans accounting for one-third of the total proteins. It contains three polypeptide α-chains and each polypeptide chain has a repeating Gly–X–Y triplet. Three polypeptide α-chains in the triple helix are held together by interchain hydrogen bonds.
According to the structure and properties of ECM, collagens can be categorized into classical fibrillar and network-forming collagen, fibril-associated collagens with interrupted triple helices, membrane-associated collagens with interrupted triple helices (MACITs), and multiple triple-helix domains and interruptions. At least 28 different types of collagens have been identified in vertebrates. Among these, the triple helix of Type I collagen has no imperfections and it has predominant role in tissue. However, others such as MACIT have numerous interruptions in the triple helix and do not self-assemble into fibrils. Type IV collagen is the network-forming collagen, forming an interlaced network at basement membrane (BM), performing an important molecular filtration function. Fibroblasts are the cells responsible for secreting collagen along with ECM, which form the structural framework of tissues in animals and play an important role in tissue repair.
| > Tumor-Associated Fibroblasts|| |
A modulated fibroblast exhibiting features of smooth muscle cells has been initially identified by means of electron microscopy in granulation tissue of healing wounds. Different factors involved in the process of differentiation of fibroblasts into myofibroblasts are transforming growth factor-β (TGF-β) family – platelet-derived growth factor, insulin-like growth factor II, and interleukin-4. They induce proliferation via secretion of Activin A and promote invasion throughout the secretion of MMPs. The invasion beyond the BM is necessary to evoke a myofibroblastic stromal reaction.
Petrov et al. suggested the dose-dependent production of soluble and nonsoluble collagen by TGF-β during differentiation of cardiac fibroblasts to myofibroblasts. Their appearance has also been found associated with transformation of laryngeal squamous intraepithelial lesions to SCC.
The role of cancer-associated myofibroblasts influencing tumor growth and correlating with poor clinical prognosis has increased the interest of many researchers in their cellular origins, their regulation, and their role in repair and disease.
Hinz et al. studied the role of myofibroblasts secreting ADAM-9S in both fibrogenic process and hepatic tumors, where ADAM-9S represents an important mediator of tumor–stroma interaction and a determinant of cancer cell ability to invade and colonize the liver.
In breast cancer, as suggested by Provenzano et al. and Levental et al., tumor-associated ECM exhibits the architecture and other physical properties that are fundamentally different from that of the normal tissue stroma. Rather than relaxed nonoriented fibrils, the Collagen I in breast tumors is highly linearized with its orientation directed adjacent to the epithelium or projecting perpendicularly into the tissue. Diseased tissue in breast cancer is typically ten times stiffer than normal stroma. This increase in tissue stiffness can be attributed to excess activities of lysyl oxidase (LOX), which cross-links collagen fibers and other ECM components, leading to upregulation of LOX expression as a poor prognostic marker in various cancers, including head-and-neck cancer, promoting tumor cell invasion and progression. In a recent study, the LOX activity has been found upregulated in cases of oral submucous fibrosis turning into OSCC due to the alterations of fibroblasts to tumor-associated fibroblasts [Table 1].
Cell migration from the primary tumor and invasion into adjacent connective tissue requires a proteolytic modification of the ECM, migration, and loss of cell–cell adhesion. Hypoxia-inducible factor-activating proteolysis includes cathepsin D, urokinase-type plasminogen-activator receptor, and MMP2. Factors stimulating migration are phosphoglucose isomerase/autocrine motility factor, TGF, and the spreading factor c-Met. Cancer stem cells (CSCs) also participate in angiogenesis and lymphangiogenesis through various factors including blood endothelial cells, CSCs, lymphatic endothelial cells, mesenchymal stem cells, and tumor-associated macrophages [Figure 1].,
| > Conclusion|| |
Hence, it is proposed that collagen can act as a double-edged sword, behaving as tumor suppressor at early stages and tumor promoters at late stages of tumor progression. Furthermore, collagen being the most important architecture can be no longer considered as a static and passive background upon which metastasis takes place. To elucidate the changes in collagen structure and the related biomechanical forces to modulate tumor invasion and metastasis, deciphering the “collagen code” in cancer progression is an intriguing field for intensive investigation.
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Conflicts of interest
There are no conflicts of interest.
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