ISSN: 2008-2258
Vol 15, No 2 (2022): Spring
Cartilage Oligomeric Matrix Protein as a Non Invasive Biomarker for Diagnosis of Hepatocellular Carcinoma in Patients with Liver Cirrhosis
Gastroenterology and Hepatology from Bed to Bench,
,
https://doi.org/10.22037/ghfbb.vi.2407
Abstract
Background: Cartilage oligomeric matrix protein (COMP) is known to promote fibrosis in various tissues. Emerging evidence shows that COMP plays critical roles in tumor development. It can serve as a fibrosis and cancer biomarkers.
Aim: To evaluate serum COMP as a diagnostic marker for HCC in patients with cirrhosis and to correlate it with other parameters of disease progression.
Subjects and Methods: The study included 24 subjects who serve as healthy control, 24 cirrhotic patients without HCC and 24 HCC patients on top of cirrhosis.All participants were subjected to determination of liver function tests, AFP, calculation of fibrotic indices (APRI and FIB-4) and serum COMP by ELISA.
Results: COMP was significantly increased in cirrhotic patients when compared to healthy controls and in HCC patients when compared to cirrhotic patients and healthy controls. A significant positive correlation was observed between COMP and APRI and FIB-4 in cirrhotic and HCC patients. Based on receiver operating characteristic (ROC) curve analysis, COMP had an area under curve (AUC) of 0.943 with 87.5% sensitivity and 79.2% specificity for diagnosis of HCC in cirrhotic patients. On combination with AFP, the sensitivity was increased to 100%.
Conclusion: COMP might act as a promising non-invasive biomarker for HCC either alone or in combination with AFP. It was correlated with the degree of fibrosis and was associated with advanced cancer staging.
Keywords:
- Cartilage Oligomeric Matrix Protein
- Hepatocellular Carcinoma
- Liver Cirrhosis
References
Refrences
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2. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet 2018; 391:1301–14. https://doi.org/10.1016/S0140-6736(18)30010-2.
3. Akinyemiju T, Abera S, Ahmed M , Alam N, Alemayohu MA, Allen C, et al. The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level. JAMA Oncol 2017; 3:1683-91. https://doi.org/10.1001/jamaoncol.2017.3055.
4. Ramakrishna G, Rastogi A, Trehanpati N, Sen B, Khosla R, Sarin SK . From cirrhosis to hepatocellular carcinoma: new molecular insights on inflammation and cellular senescence. Liver Cancer 2013; 2 (3-4): 367-383.
5. Gomaa AI, Hashim MS, Waked I. Comparing staging systems for predicting prognosis and survival in patients with hepatocellular carcinoma in Egypt. PLoS One 2014; 9(3): e90929. doi: 10.1371/journal.pone.0090929, accessed on 25/10/2020.
6. Nordenstedt H, White DL, El-Serag HB. The changing pattern of epidemiology in hepatocellular carcinoma. Dig Liver Dis 2010;42(3): S206-S214.
7. European Association For The Study Of The Liver; European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56: 908–943.
8. Halász K, Kassner A, Mörgelin M, Heinegård D. COMP acts as a catalyst in collagen fibrillogenesis. J BiolChem 2007; 282: 31166-31173 .
9. Hedbom E, Antonsson P, Hjerpe A, Aeschlimann D, Paulsson M, Rosa-Pimentel E, et al. Cartilage matrix proteins. An acidic oligomeric protein (COMP) detected only in cartilage.JBiol 1992; Chem.267: 6132–6136.
10. Tseng S, Reddi AH, Di Cesare PE. Cartilage Oligomeric Matrix Protein (COMP): a biomarker of arthritis. Biomark Insights 2009; 4: 33–44.
11. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004; 127(5 Suppl 1): S35–50.
12. Tilghman RW, Blais EM, Cowan CR, Sherman NE, Grigera PR, Jeffery ED, et al. Matrix rigidity regulates cancer cell growth by modulating cellular metabolism and protein synthesis. PLoS One 2012; 7 (5): e37231.
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19. Vallet-Pichard A , Mallet V, Nalpas B, Verkarre V, Nalpas A, Dhalluin-Venier V, et al. Pol S. FIB‐4: An inexpensive and accurate marker of fibrosis in HCV infection. comparison with liver biopsy and fibrotest. Journal of Hepatology AASLD 2007; 46 (1): 32-36.
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25. Hu B, Tian X, Sun J, Meng X. Evaluation of individual and combined applications of serum biomarkers for diagnosis of hepatocellular carcinoma: a meta-analysis. Int J MolSci 2013; 14 (12): 23559-23580.
26. Vuga LJ, Milosevic J, Pandit K, Ben-Yehudah A, Chu Y, RichardsT, et al. Cartilage oligomeric matrix protein in idiopathic pulmonary fibrosis.PLoS One 2013;8 (12): e83120.
27. Li Q, Wang C, Wang Y, Sun L, Liu Z, Wang L, et al. HSCs-derived COMP drives hepatocellular carcinoma progression by activating MEK/ERK and PI3K/AKT signaling pathways. Journal of Experimental & Clinical Cancer Research 2018; 37(1): 231.
28. Zachou K, Gabeta S, Gatselis NK, Norman GL, Dalekos GN. Cartilage oligomeric matrix protein on the spot for liver fibrosis evaluation: Too early or too late? European Journal of Internal Medicine 2017; 43: e48-e49
29. Scott LF. Hepatic Fibrosis. In: Eugene R Schiff, Michael F Sorrell, Willis C Maddrey, editors. Schiff’s Diseases of the Liver. 11th edition. Wiley-Blackwell, Singapore,2012; p: 297–305.
30. Zachou K, Gabeta S, Shums Z, Gatselis NK, Koukoulis GK, Norman GL, et al. COMP serum levels: a new non-invasive biomarker of liver fibrosis in patients with chronic viral hepatitis. Eur J Intern Med 2017; 38: 83–88.
31. Magdaleno F, Arriazu E, Ruiz de Galarreta M, Chen Y, Ge X, et al. Cartilage oligomeric matrix protein participates in the pathogenesis of liver fibrosis. J Hepatol 2016; 65 (5): 963–971.
32. Andréasson K, Waldenström J, Westin J, Norrgren H, Jönsson G, Nyström K, et al. Cartilage oligomeric matrix protein associates with hepatic inflammation and fibrosis in hepatitis C virus infection. J Hepatol 2017; 67 (3): 649-651.
33. Xiao Y, Kleeff J, Guo J, Gazdhar A, Liao Q, Di Cesare, et al. Cartilage oligomeric matrix protein expression in hepatocellular carcinoma and the cirrhotic liver. J. Gastroenterol. Hepatol 2004; 19: 296–302.
34. Kim BG, An HJ, Kang S, Choi YP, GAO MQ, Park H, et al. Laminin-332-rich tumor microenvironment for tumor invasion in the interface zone of breast cancer. Am J Pathol 2011; 178: 373-381.
35. Kang N, Gores GJ, Shah VH. Hepatic stellate cells: partners in crime for liver metastases? Hepatology 2011; 54(2): 707–713.
36. Cabibbo G, Enea M , Attanasio M, Bruix J, Craxì A, Cammà C. A meta-analysis of survival rates of untreated patients in randomized clinical trials of hepatocellular carcinoma . Hepatology 2010; 51: 1274–1283.
37. Riessen R, Fenchel M, Chen H, Axel DI, Karsch KR, Lawler J. Cartilage oligomeric matrix protein (thrombospondin-5) is expressed by human vascular smooth muscle cells. ArteriosclerThrombVascBiol 2001; 21: 47–54.
38. Canfield AE, Farrington C, Dziobon MD, Boot-Handford RP, Heagerty AM, Kumar SN, et al. The involvement of matrix glycoproteins in vascular calcification and fibrosis: an immunohistochemical study. J. Pathol 2002; 196: 228–234.
39. Clark P. Serum markers for hepatocellular carcinoma. Clin Liver Dis; 2016 8 (2): 29-33.
1. Yu LX and Schwabe RF. The gut microbiome and liver cancer: mechanisms and clinical translation. Nature Reviews Gastroenterology & Hepatology 2017; 14(9):527–539.
2. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet 2018; 391:1301–14. https://doi.org/10.1016/S0140-6736(18)30010-2.
3. Akinyemiju T, Abera S, Ahmed M , Alam N, Alemayohu MA, Allen C, et al. The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level. JAMA Oncol 2017; 3:1683-91. https://doi.org/10.1001/jamaoncol.2017.3055.
4. Ramakrishna G, Rastogi A, Trehanpati N, Sen B, Khosla R, Sarin SK . From cirrhosis to hepatocellular carcinoma: new molecular insights on inflammation and cellular senescence. Liver Cancer 2013; 2 (3-4): 367-383.
5. Gomaa AI, Hashim MS, Waked I. Comparing staging systems for predicting prognosis and survival in patients with hepatocellular carcinoma in Egypt. PLoS One 2014; 9(3): e90929. doi: 10.1371/journal.pone.0090929, accessed on 25/10/2020.
6. Nordenstedt H, White DL, El-Serag HB. The changing pattern of epidemiology in hepatocellular carcinoma. Dig Liver Dis 2010;42(3): S206-S214.
7. European Association For The Study Of The Liver; European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56: 908–943.
8. Halász K, Kassner A, Mörgelin M, Heinegård D. COMP acts as a catalyst in collagen fibrillogenesis. J BiolChem 2007; 282: 31166-31173 .
9. Hedbom E, Antonsson P, Hjerpe A, Aeschlimann D, Paulsson M, Rosa-Pimentel E, et al. Cartilage matrix proteins. An acidic oligomeric protein (COMP) detected only in cartilage.JBiol 1992; Chem.267: 6132–6136.
10. Tseng S, Reddi AH, Di Cesare PE. Cartilage Oligomeric Matrix Protein (COMP): a biomarker of arthritis. Biomark Insights 2009; 4: 33–44.
11. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004; 127(5 Suppl 1): S35–50.
12. Tilghman RW, Blais EM, Cowan CR, Sherman NE, Grigera PR, Jeffery ED, et al. Matrix rigidity regulates cancer cell growth by modulating cellular metabolism and protein synthesis. PLoS One 2012; 7 (5): e37231.
13. Xiao Y, Kleeff J, Guo J, Gazdhar A, Liao Q, Di Cesare PE, et al. Cartilage oligomeric matrix protein expression in hepatocellular carcinoma and the cirrhotic liver. J. Gastroenterol. Hepatol 2004; 19: 296–302.
14. Norman GL, Gatselis NK, Shums Z, Liaskos c, Bogdanos DP, Koukoulis GK, et al. Cartilage oligomeric matrix protein: a novel non-invasive marker for assessing cirrhosis and risk of hepatocellular carcinoma. World J Hepatol 2015; 7:1875–1883.
15. Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, et al. EASL Panel of Experts on HCC. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona 2000 EASL conference. J Hepatol 2001; 35 (3): 421-430.
16. Sebastian A and Varghese SM. Fuzzy logic for Child-Pugh classification of patients with cirrhosis of liver. Journal International Conference on Information Science 2016; 168-171. DOI: 10.1109/INFOSCI.2016.7845320. accessed on 18/9/2018.
17. Adhoute X, Penaranda G, Raoul JL, Le Treut P, Bollon E, Hardwigsen J, et al. Usefulness of staging systems and prognostic scores for hepatocellular carcinoma treatments. World J Hepatol 2016; 8 (17): 703.
18. Loaeza-del-Castillo A, Paz-Pineda F, Oviedo-Cárdenas E, Sánchez-Avila F, Vargas-Vorácková F. AST to platelet ratio index (APRI) for the noninvasive evaluation of liver fibrosis. Annals of Hepatology 2008; 7(4): 350-357
19. Vallet-Pichard A , Mallet V, Nalpas B, Verkarre V, Nalpas A, Dhalluin-Venier V, et al. Pol S. FIB‐4: An inexpensive and accurate marker of fibrosis in HCV infection. comparison with liver biopsy and fibrotest. Journal of Hepatology AASLD 2007; 46 (1): 32-36.
20. Omata M, Lesmana LA, Tateishi R, Chen PJ, Lin SM, Yoshida H, et al. Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma. HepatolInt 2010; 4(2): 439-474.
21. Zhu RX, Seto WK, Lai CL, Yuen MF. Epidemiology of hepatocellular carcinoma in the Asia-Pacific region. Gut Liver 2016; 10(3): 332–339.
22. Simmons OL, Feng Y, Parikh ND, Singal AG. Primary care provider practice patterns and parriers to hepatocellular carcinoma surveillance. Clin Gastro enteral Hepatol 2019; 17 (4): 766-773.
23. Njei B, Rotman Y, Ditah I, Lim JK. Emerging trends in hepatocellular carcinoma incidence and mortality. Hepatology 2015; 61 (1): 191-199.
24. Lopez JB. Recent developments in the first detection of hepatocellular carcinoma.ClinBiochem Rev 2005; 26: 65-79.
25. Hu B, Tian X, Sun J, Meng X. Evaluation of individual and combined applications of serum biomarkers for diagnosis of hepatocellular carcinoma: a meta-analysis. Int J MolSci 2013; 14 (12): 23559-23580.
26. Vuga LJ, Milosevic J, Pandit K, Ben-Yehudah A, Chu Y, RichardsT, et al. Cartilage oligomeric matrix protein in idiopathic pulmonary fibrosis.PLoS One 2013;8 (12): e83120.
27. Li Q, Wang C, Wang Y, Sun L, Liu Z, Wang L, et al. HSCs-derived COMP drives hepatocellular carcinoma progression by activating MEK/ERK and PI3K/AKT signaling pathways. Journal of Experimental & Clinical Cancer Research 2018; 37(1): 231.
28. Zachou K, Gabeta S, Gatselis NK, Norman GL, Dalekos GN. Cartilage oligomeric matrix protein on the spot for liver fibrosis evaluation: Too early or too late? European Journal of Internal Medicine 2017; 43: e48-e49
29. Scott LF. Hepatic Fibrosis. In: Eugene R Schiff, Michael F Sorrell, Willis C Maddrey, editors. Schiff’s Diseases of the Liver. 11th edition. Wiley-Blackwell, Singapore,2012; p: 297–305.
30. Zachou K, Gabeta S, Shums Z, Gatselis NK, Koukoulis GK, Norman GL, et al. COMP serum levels: a new non-invasive biomarker of liver fibrosis in patients with chronic viral hepatitis. Eur J Intern Med 2017; 38: 83–88.
31. Magdaleno F, Arriazu E, Ruiz de Galarreta M, Chen Y, Ge X, et al. Cartilage oligomeric matrix protein participates in the pathogenesis of liver fibrosis. J Hepatol 2016; 65 (5): 963–971.
32. Andréasson K, Waldenström J, Westin J, Norrgren H, Jönsson G, Nyström K, et al. Cartilage oligomeric matrix protein associates with hepatic inflammation and fibrosis in hepatitis C virus infection. J Hepatol 2017; 67 (3): 649-651.
33. Xiao Y, Kleeff J, Guo J, Gazdhar A, Liao Q, Di Cesare, et al. Cartilage oligomeric matrix protein expression in hepatocellular carcinoma and the cirrhotic liver. J. Gastroenterol. Hepatol 2004; 19: 296–302.
34. Kim BG, An HJ, Kang S, Choi YP, GAO MQ, Park H, et al. Laminin-332-rich tumor microenvironment for tumor invasion in the interface zone of breast cancer. Am J Pathol 2011; 178: 373-381.
35. Kang N, Gores GJ, Shah VH. Hepatic stellate cells: partners in crime for liver metastases? Hepatology 2011; 54(2): 707–713.
36. Cabibbo G, Enea M , Attanasio M, Bruix J, Craxì A, Cammà C. A meta-analysis of survival rates of untreated patients in randomized clinical trials of hepatocellular carcinoma . Hepatology 2010; 51: 1274–1283.
37. Riessen R, Fenchel M, Chen H, Axel DI, Karsch KR, Lawler J. Cartilage oligomeric matrix protein (thrombospondin-5) is expressed by human vascular smooth muscle cells. ArteriosclerThrombVascBiol 2001; 21: 47–54.
38. Canfield AE, Farrington C, Dziobon MD, Boot-Handford RP, Heagerty AM, Kumar SN, et al. The involvement of matrix glycoproteins in vascular calcification and fibrosis: an immunohistochemical study. J. Pathol 2002; 196: 228–234.
39. Clark P. Serum markers for hepatocellular carcinoma. Clin Liver Dis; 2016 8 (2): 29-33.
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