Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 
REVIEW ARTICLE
Ahead of print publication  

Deciphering the “Collagen code” in tumor progression


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

Correspondence Address:
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
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_489_17

 > Abstract 


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



How to cite this URL:
Gupta AA, Kheur S, Palaskar SJ, Narang BR. Deciphering the “Collagen code” in tumor progression. J Can Res Ther [Epub ahead of print] [cited 2019 Nov 18]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=257726




 > Introduction Top


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.[1] 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.[2] Much effort has already been devoted in determining how cellular components of the niche initiate and promote cancer development.[3] 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.[4]

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.[3] 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.[5] And as we age, there is a reduction of collagen deposition and increased matrix metalloproteinase (MMP) activity.[6]

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.[7] 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 Top


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.[8] At least 28 different types of collagens have been identified in vertebrates.[9] Among these, the triple helix of Type I collagen has no imperfections and it has predominant role in tissue.[10] However, others such as MACIT have numerous interruptions in the triple helix and do not self-assemble into fibrils.[9] Type IV collagen is the network-forming collagen, forming an interlaced network at basement membrane (BM),[11] 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 Top


A modulated fibroblast exhibiting features of smooth muscle cells[12] 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.[13] They induce proliferation via secretion of Activin A and promote invasion throughout the secretion of MMPs.[14] The invasion beyond the BM is necessary to evoke a myofibroblastic stromal reaction.[15]

Petrov et al. suggested the dose-dependent production of soluble and nonsoluble collagen by TGF-β during differentiation of cardiac fibroblasts to myofibroblasts.[16] Their appearance has also been found associated with transformation of laryngeal squamous intraepithelial lesions to SCC.[17]

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.[18]

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.[19]

In breast cancer, as suggested by Provenzano et al. and Levental et al.,[20] 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.[20] Diseased tissue in breast cancer is typically ten times stiffer than normal stroma.[21] 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,[22] promoting tumor cell invasion and progression.[21] 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].[23]
Table 1: Cancer-associated fibroblasts in oral squamous cell carcinoma

Click here to view


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].[30],[31]
Figure 1: Tumor Microenvironment response to tumor cell invasion

Click here to view



 > Conclusion Top


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.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Bissell MJ, Hall HG, Parry G. How does the extracellular matrix direct gene expression? J Theor Biol 1982;99:31-68.  Back to cited text no. 1
    
2.
Bissell MJ, Radisky D. Putting tumours in context. Nat Rev Cancer 2001;1:46-54.  Back to cited text no. 2
    
3.
Bhowmick NA, Neilson EG, Moses HL. Stromal fibroblasts in cancer initiation and progression. Nature 2004;432:332-7.  Back to cited text no. 3
    
4.
Cox TR, Erler JT. Remodeling and homeostasis of the extracellular matrix: Implications for fibrotic diseases and cancer. Dis Model Mech 2011;4:165-78.  Back to cited text no. 4
    
5.
Zhu GG, Risteli L, Mäkinen M, Risteli J, Kauppila A, Stenbäck F, et al. Immunohistochemical study of type I collagen and type I pN-collagen in benign and malignant ovarian neoplasms. Cancer 1995;75:1010-7.  Back to cited text no. 5
    
6.
Norton WH, Ledin J, Grandel H, Neumann CJ. HSPG synthesis by Zebrafish ext2 and extl3 is required for fgf10 signalling during limb development. Development 2005;132:4963-73.  Back to cited text no. 6
    
7.
Silverman S Jr. Oral Cancer. 4th ed. London: B.C American Cancer Society, Decker Inc.; 1998.  Back to cited text no. 7
    
8.
Shoulders MD, Raines RT. Collagen structure and stability. Annu Rev Biochem 2009;78:929-58.  Back to cited text no. 8
    
9.
Kadler KE, Baldock C, Bella J, Boot-Handford RP. Collagens at a glance. J Cell Sci 2007;120:1955-8.  Back to cited text no. 9
    
10.
Boot-Handford RP, Tuckwell DS. Fibrillar collagen: The key to vertebrate evolution? A tale of molecular incest. Bioessays 2003;25:142-51.  Back to cited text no. 10
    
11.
Kalluri R. Basement membranes: Structure, assembly and role in tumour angiogenesis. Nat Rev Cancer 2003;3:422-33.  Back to cited text no. 11
    
12.
Gabbiani G, Ryan GB, Majne G. Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction. Experientia 1971;27:549-50.  Back to cited text no. 12
    
13.
Lúcio PS, Cavalcanti AL, Alves PM, Godoy GP, Nonaka CF. Myofibroblasts and their relationship with oral squamous cell carcinoma. Braz J Otorhinolaryngol 2013;79:112-8.  Back to cited text no. 13
    
14.
Rothouse LS, Majack RA, Fay JT. An ameloblastoma with myofibroblasts and intracellular septate junctions. Cancer 1980;45:2858-63.  Back to cited text no. 14
    
15.
Shirol PD, Shirol DD. Myofibroblasts in Health and Disease. Int J Oral Maxillofac Pathol 2012;3:23-7.  Back to cited text no. 15
    
16.
Petrov VV, Fagard RH, Lijnen PJ. Stimulation of collagen production by transforming growth factor-beta1 during differentiation of cardiac fibroblasts to myofibroblasts. Hypertension 2002;39:258-63.  Back to cited text no. 16
    
17.
Tsujino T, Seshimo I, Yamamoto H, Ngan CY, Ezumi K, Takemasa I, et al. Stromal myofibroblasts predict disease recurrence for colorectal cancer. Clin Cancer Res 2007;13:2082-90.  Back to cited text no. 17
    
18.
Hinz B. Formation and function of the myofibroblast during tissue repair. J Invest Dermatol 2007;127:526-37.  Back to cited text no. 18
    
19.
Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G, et al. The myofibroblast: One function, multiple origins. Am J Pathol 2007;170:1807-16.  Back to cited text no. 19
    
20.
Provenzano PP, Eliceiri KW, Campbell JM, Inman DR, White JG, Keely PJ, et al. Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Med 2006;4:38.  Back to cited text no. 20
    
21.
Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 2009;139:891-906.  Back to cited text no. 21
    
22.
Le QT, Harris J, Magliocco AM, Kong CS, Diaz R, Shin B, et al. Validation of lysyl oxidase as a prognostic marker for metastasis and survival in head and neck squamous cell carcinoma: Radiation therapy oncology group trial 90-03. J Clin Oncol 2009;27:4281-6.  Back to cited text no. 22
    
23.
Trivedy C, Warnakulasuriya KA, Hazarey VK, Tavassoli M, Sommer P, Johnson NW, et al. The upregulation of lysyl oxidase in oral submucous fibrosis and squamous cell carcinoma. J Oral Pathol Med 1999;28:246-51.  Back to cited text no. 23
    
24.
Lin NN, Wang P, Zhao D, Zhang FJ, Yang K, Chen R, et al. Significance of oral cancer-associated fibroblasts in angiogenesis, lymphangiogenesis, and tumor invasion in oral squamous cell carcinoma. J Oral Pathol Med 2017;46:21-30.  Back to cited text no. 24
    
25.
Kayamori K, Katsube K, Sakamoto K, Ohyama Y, Hirai H, Yukimori A, et al. NOTCH3 is induced in cancer-associated fibroblasts and promotes angiogenesis in oral squamous cell carcinoma. PLoS One 2016;11:e0154112.  Back to cited text no. 25
    
26.
Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer 2016;16:582-98.  Back to cited text no. 26
    
27.
Li H, Zhang J, Chen SW, Liu LL, Li L, Gao F, et al. Cancer-associated fibroblasts provide a suitable microenvironment for tumor development and progression in oral tongue squamous cancer. J Transl Med 2015;13:198.  Back to cited text no. 27
    
28.
Klobukowska HJ, Munday JS. High numbers of stromal cancer-associated fibroblasts are associated with a shorter survival time in cats with oral squamous cell carcinoma. Vet Pathol 2016;53:1124-30.  Back to cited text no. 28
    
29.
Augsten M. Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment. Front Oncol 2014;4:62.  Back to cited text no. 29
    
30.
Li S, Li Q. Cancer stem cells and tumor metastasis (Review). Int J Oncol 2014;44:1806-12.  Back to cited text no. 30
    
31.
Pouysségur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 2006;441:437-43.  Back to cited text no. 31
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1]



 

 
Top
 
 
  Search
 
     Search Pubmed for
 
    -  Gupta AA
    -  Kheur S
    -  Palaskar SJ
    -  Narang BR
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  >Abstract>Introduction>Collagen in Health>Tumor-Associated...>Conclusion>Article Figures>Article Tables
  In this article
>References

 Article Access Statistics
    Viewed341    
    PDF Downloaded20    

Recommend this journal