Indan Journal of Medical Research Indan Journal of Medical Research Indan Journal of Medical Research Indan Journal of Medical Research
  Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login  
  Home Print this page Email this page Small font sizeDefault font sizeIncrease font size Users Online: 1285       

   Table of Contents      
COMMENTARY
Year : 2017  |  Volume : 146  |  Issue : 3  |  Page : 298-300

Molecular interphase between extracellular matrix & cancer cells


Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160 012, India

Date of Submission30-Sep-2016
Date of Web Publication18-Jan-2018

Correspondence Address:
Kim Vaiphei
Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160 012
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmr.IJMR_1601_16

Rights and Permissions

How to cite this article:
Vaiphei K. Molecular interphase between extracellular matrix & cancer cells. Indian J Med Res 2017;146:298-300

How to cite this URL:
Vaiphei K. Molecular interphase between extracellular matrix & cancer cells. Indian J Med Res [serial online] 2017 [cited 2020 Oct 23];146:298-300. Available from: https://www.ijmr.org.in/text.asp?2017/146/3/298/223627

Tumorigenesis and tumour progression are highly complex biological processes where normal control over cell growth is modified by various genetic mutations[1]. Cancer progression depends on tumour cell per se and the microenvironment in which tumour cells are embedded. Interaction between tumour cell and microenvironment results in the activation of various molecular pathways including angiogenesis as a mode to supply essential nutrients[2]. Concept of a permissive environment in promoting tumour growth has interesting history. In the early 1850s, the German pathologist and scientist Rudolf Ludwig Carl Virchow had hypothesized the possible roles of inflammatory cells and abnormal extracellular matrix (ECM) biosynthesis on tumour progression[3]. A few years later, an English surgeon named Sir Stephen Paget postulated the “Seed and Soil” theory in 1889[4]. His hypothesis was contradicted by many scientists. Much later, his view has been supported and re-confirmed by numerous researchers. The potential of tumour cells to metastasize depends on the interactions with the tumour microenvironment factors that promote tumour growth, survival, angiogenesis, invasion and metastasis[5]. Several years down after, Dvorak[6] re-described that the desmoplastic stroma or the granulation tissue surrounding tumour cells did not heal, unlike other inflammatory granulation tissue. He further emphasized importance of certain key factors present or expressed by the reactive or desmoplastic stroma which include cancer-associated fibroblasts (CAFs), inflammatory cells, cells constituting blood vessels and ECM[7]. These mutual interactions and cross-talks between tumour cells and stroma promote tumour progression in many ways. A cancer cell has the propensity to secret various types of growth factors, such as transforming growth factor beta (TGF-β), epidermal growth factor (EGF), basic fibroblast growth factor (FGF-2) and vascular endothelial growth factor (VEGF). Under the influence of these many growth factors, a cancer cell may change the property of microenvironment. Fibroblasts get converted to large spindle-shaped CAFs acquiring expression for alpha smooth muscle actin associated with increased proliferative index and rapid collagen biosynthesis, producing an altered or modified ECM[8]. On the flip side, the CAF of the specialized ECM secrets increased amount of tenascin C, thereby reducing adhesive property of the cancer cells promoting their motility and metastasis. CAFs are also documented to secrete (i) proteases that degrade ECM releasing cytokines facilitating tumour angiogenesis and metastasis, (ii) insulin-like growth factor, and (iii) hepatocyte growth factor, thereby increasing and promoting tumour cell survival and motility[9]. Inflammatory cell present in ECM induces enhanced cytokines and chemokines production by tumour cells[10], which appears to be a counter-intuitive function as leucocytes have the property to attack and destroy tumour cells. Recruitment of immune cells facilitates further tumour growth and metastasis via secretion of matrix-degrading enzymes such as matrix metalloproteinases (MMPs), urokinase-type plasminogen activator (uPA) and heparanases[11].

MMPs are calcium-dependent endopeptidases which require a coordinated activity with zinc ion to mediate catalysis. The active function of MMPs is to mediate degradation of different ECM components[12]. The biochemically active components of MMPs and their enzyme activities have been classified into five major groups[13]: (i) true collagenases that have the property to cleave major fibrillar collagens; (ii) gelatinases that proteolyse denatured collagen; (iii) stromelysin which is the most diverse component that has the capacity to activate other MMPs; (iv) the next group is the matrilysins that may be either in secreted form or intracellular. The active cytoplasmic form helps in maintenance of innate immune system by activating defensin; and (v) the last major group encompasses collagen, cell surface molecules and bioactive molecules. MMPs participate almost in every biological processes involving remodelling of ECM, embryo implantation to tissue necrosis. There are certain MMP isoforms expressed in non-primates with minimal knowledge of their function and structures[14].

Physiological transcription of MMPs is governed by tightly regulated pathways and detectable in very low amount. Further regulation of MMP activity is post-translational by modifying the production of zymogens required for activation and co-expression of tissue inhibitors of metalloproteinases[15]. Any situation resulting in dysregulation of the regulatory mechanisms may lead to worsening of a given disease condition. Despite the concept of a clear association between MMPs and cancer progression, there is still a big lapse in the field of translational research in objectiveness of the roles played by MMPs, basically due to failures of the MMP inhibitors in multiple phase III trial[16]. The reasons for the failure to inhibit the MMPs may presumably be explainable hypothetically for various reasons, but the two critical issues are lack of specificity and dose-limiting side effects that are poorly understood. Some potential inhibitors recently recognized include MT1-MMPI, MMP-7 inhibitors, FGF-2 antagonist PTX3 and all-trans retinoic acid[17]. Increased MMP levels within a tumour may be the tumour cells or peri-tumoural activated fibroblasts or inflammatory cells, and the serum concentration of specific MMP has been described to be enhanced in certain select cancers[17] and body fluids[18].

There are limited reports on pancreatic cancer where raised MMP-2 plasma levels have been observed[19],[20]. The study[21] in this issue, however, failed to find any significant relationship between plasma MMP-2 level with tumour stage and disease outcome. The authors have observed a significant correlation between MMP-2 plasma level with plasma carbohydrate antigen (CA) 19-9. Patients who had tumour recurrence with distant metastasis after surgery showed higher plasma levels of both MMP-2 and CA19-9 compared to patients having only local recurrence. Moreover, patients with no recurrent disease at three months post-surgery exhibited low MMP-2 values. The authors also observed a positive correlation between MMP-2 levels in plasma and tumour tissue. The study highlighted the important implication of serum MMP-2 in pancreatic cancer in predicting tumour outcome. This observation however, requires further verification in more number of randomly selected cancer patients before and after surgery.

In conclusion, MMPs including MMP-2 remain a cryptic but viable biomarker in cancer diagnosis and in assessing the treatment outcome. The futuristic translational research for therapeutically implacable MMP inhibitors to be clinically successful, the target MMP needs to be identified and characterized at molecular level. MMP inhibitor(s) need(s) to be highly selective so that it can produce the desired effect. Moreover, it also needs to be a highly specific biomarker having the property of selective accumulation in the targeted diseased organ with no or minimal adverse clinical effect.



 
   References Top

1.
Vogelstein B, Kinzler KW. The multistep nature of cancer. Trends Genet 1993; 9 : 138-41.  Back to cited text no. 1
    
2.
Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 2011; 144 : 646-74.  Back to cited text no. 2
    
3.
Virchow R. Die krankhaften geschwülste. 1st ed. Berlin: August Hirschwald; 1863.  Back to cited text no. 3
    
4.
Paget S. The distribution of secondary growths in cancer of the breast. Lancet 1889; 133 : 571-3.  Back to cited text no. 4
    
5.
Paget S. The distribution of secondary growths in cancer of the breast 1889. Cancer Metastasis Rev 1989; 8 : 98-101.  Back to cited text no. 5
    
6.
Dvorak HF. Tumors: Wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 1986; 315 : 1650-9.  Back to cited text no. 6
    
7.
Dvorak HF. Tumors: Wounds that do not heal-redux. Cancer Immunol Res 2015; 3 : 1-11.  Back to cited text no. 7
    
8.
Lazard D, Sastre X, Frid MG, Glukhova MA, Thiery JP, Koteliansky VE, et al. Expression of smooth muscle-specific proteins in myoepithelium and stromal myofibroblasts of normal and malignant human breast tissue. Proc Natl Acad Sci U S A 1993; 90 : 999-1003.  Back to cited text no. 8
    
9.
Mueller MM, Fusenig NE. Friends or foes-bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 2004; 4 : 839-49.  Back to cited text no. 9
    
10.
Coussens LM, Werb Z. Inflammation and cancer. Nature 2002; 420 : 860-7.  Back to cited text no. 10
    
11.
Bloomston M, Zervos EE, Rosemurgy AS 2nd. Matrix metalloproteinases and their role in pancreatic cancer: A review of preclinical studies and clinical trials. Ann Surg Oncol 2002; 9 : 668-74.  Back to cited text no. 11
    
12.
Cathcart J, Pulkoski-Gross A, Cao J. Targeting matrix metalloproteinases in cancer: Bringing new life to old ideas. Genes Dis 2015; 2 : 26-34.  Back to cited text no. 12
    
13.
Roy R, Yang J, Moses MA. Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer. J Clin Oncol 2009; 27 : 5287-97.  Back to cited text no. 13
    
14.
Buckley JJ, Jessen JR. Matrix metalloproteinase function in non-mammalian model organisms. Front Biosci (Schol Ed) 2015; 7 : 168-83.  Back to cited text no. 14
    
15.
Whittaker M, Floyd CD, Brown P, Gearing AJ. Design and therapeutic application of matrix metalloproteinase inhibitors. Chem Rev 1999; 99 : 2735-76.  Back to cited text no. 15
    
16.
Shay G, Lynch CC, Fingleton B. Moving targets: Emerging roles for MMPs in cancer progression and metastasis. Matrix Biol 2015; 44-46 : 200-6.  Back to cited text no. 16
    
17.
Choi JH, Kim H, Choi JH, Choi JW, Oh BK. Signal enhancement of silicon nanowire-based biosensor for detection of matrix metalloproteinase-2 using DNA-Au nanoparticle complexes. ACS Appl Mater Interfaces 2013; 5 : 12023-8.  Back to cited text no. 17
    
18.
Overall CM, López-Otín C. Strategies for MMP inhibition in cancer: Innovations for the post-trial era. Nat Rev Cancer 2002; 2 : 657-72.  Back to cited text no. 18
    
19.
Nagy B, Woth G, Mérei Á, Nagy L, Lantos J, Menyhei G, et al. Perioperative time course of matrix metalloproteinase-9 (MMP-9), its tissue inhibitor TIMP-1 & S100B protein in carotid surgery. Indian J Med Res 2016; 143 : 220-6.  Back to cited text no. 19
    
20.
Xu Z, Pothula SP, Wilson JS, Apte MV. Pancreatic cancer and its stroma: A conspiracy theory. World J Gastroenterol 2014; 20 : 11216-29.  Back to cited text no. 20
    
21.
Singh N, Gupta S, Pandey RM, Sahni P, Chauhan SS, Saraya A. Prognostic significance of plasma matrix metalloprotease-2 (MMP-2) in pancreatic cancer patients. Indian J Med Res 2017; 146 : 334-40.  Back to cited text no. 21
    




 

Top
 
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
    References

 Article Access Statistics
    Viewed552    
    Printed5    
    Emailed0    
    PDF Downloaded260    
    Comments [Add]    

Recommend this journal