Hepatocellular carcinoma pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Dildar Hussain, MBBS [2]

Overview

The exact pathogenesis of hepatocellular carcinoma (HCC) is not fully understood. It is thought that HCC is mediated by either HBV infection, HCV infection, underlying cirrhotic liver disease, inflammation, necrosis, and fibrosis. On microscopic histopathological analysis, large polygonal tumor cells with granular eosinophilic cytoplasm or layered dense collagen bundles are characteristic findings of hepatocellular carcinoma.

Pathophysiology

Pathogenesis

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Major molecular events in the pathogenesis of HCC
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genomic alterations
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Epigenetic modifications
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Growthfactor pathway alterations
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gene Mutations
 
Gene Amplification
 
 
 
 
 
 
 
DNA methylation micro RNA
 
 
 
 
Micro RNA
 
 
 
 
 
LNC RNA
 
 
 
 
 
 
Major Signaling pathways
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
•TERT promoter
•TP53
•CTNNB1
•AXIN1
•AXIN2
•ATM
•RPS6KA3
•JAK1
•IL6R
•IL6ST
•ARID1
•ARID2
 
•CCND1
•FGF19
•CDKNA2A
•CDKNA2B
•AXIN1
•IRF2
•MET
 
 
 
 
 
 
 
GSTP1
•E-cadherin
•CDKNA2
•RASSF1A
•SOCS3
•MIGMT
 
 
 
 
•MiR-155
•MiR-122
•MiR-224
•MiR-21
 
 
 
 
 
•HULC
•HEIH
•Dreh
•MVIH
•HOTAIR
•MDIG
•LINE1
 
 
 
 
 
 
•Wnt/β–catenin
•Tyrosine kinase pathways
EGF
HGF/c-MET
FGF
VEGF
•IGF
•HIF1
•HIF2
•TGF β
•Hedgehog

To review the pathogenesis of HBV infection, click here.

To review the pathogenesis of HCV infection click here.

To review the pathogenesis of hepatic cirrhosis, click here.

Genetics

  • As of now there is no significant manifestation of an ordered cycle of genomic events leading to hepato-carcinogenesis. The pattern of genomic transformations exhibit huge variations often between two different HCCs from a single patient.
  • Hepatocellular carcinoma is most commonly implicated with underlying chronic hepatitis and cirrhosis, however different genes have been associated with the pathogenesis of the HCC, which are further divided into four major groups:[2][24]
  • Genes involved in the pathogenesis of hepatocellular carcinoma include:

Associated Conditions

The associated conditions with hepatocellular carcinoma are

Microscopic Pathology

  • On microscopic histopathological analysis, large polygonal tumor cells with granular eosinophilic cytoplasm or layered dense collagen bundles are characteristic findings of hepatocellular carcinoma.

Gross Pathology

On gross pathology, hepatocellular carcinoma has the following characteristic findings:[55]

  • The nodular type may be unifocal (large mass) or multifocal (when developed as a complication of cirrhosis). Tumor nodules are round to oval, grey or green (if the tumor produces bile), well circumscribed but not encapsulated.
  • In about fifty percent of the cases, the tumors are multifocal where as some authors have suggested it to be around 75 percent.
  • The portal vein is infiltrated by the poorly circumcised diffused type and the hepatic veins are rarely infiltrated.
  • Pale in relation to surrounding liver or green (due to bile secretion)
  • Hepatocelluler carcinoma. The image shows a longitudinal slice taken through the full length of the liver. (Courtesy of Ed Uthman, MD)

    Hepatocelluler carcinoma. The image shows a longitudinal slice taken through the full length of the liver.
    (Courtesy of Ed Uthman, MD)

  • The tumor is at the top, cirrhotic liver at the bottom, and a fibrous reaction in between. Hepatocellular carcinomas can have a variety of gross patterns, including multinodular / multifocal, such as this one. (Courtesy of Ed Uthman, MD)

    The tumor is at the top, cirrhotic liver at the bottom, and a fibrous reaction in between. Hepatocellular carcinomas can have a variety of gross patterns, including multinodular / multifocal, such as this one.
    (Courtesy of Ed Uthman, MD)

Microscopic Pathology

On microscopic histopathological analysis, hepatocellular carcinoma has the following characteristic findings:

  • Large polygonal tumor cells with:
  • Granular eosinophilic cytoplasm
  • Low NC ratio
  • Layered dense collagen bundles [56]

Videos

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References

  1. ↑ Röcken C, Carl-McGrath S (2001). "Pathology and pathogenesis of hepatocellular carcinoma". Dig Dis. 19 (4): 269–78. doi:10.1159/000050693. PMID 11935086.
  2. ↑ 2.0 2.1 Dhanasekaran R, Bandoh S, Roberts LR (2016). "Molecular pathogenesis of hepatocellular carcinoma and impact of therapeutic advances". F1000Res. 5. doi:10.12688/f1000research.6946.1. PMC 4870992. PMID 27239288.
  3. ↑ Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA, Friedman AH, Friedman H, Gallia GL, Giovanella BC, Grollman AP, He TC, He Y, Hruban RH, Jallo GI, Mandahl N, Meeker AK, Mertens F, Netto GJ, Rasheed BA, Riggins GJ, Rosenquist TA, Schiffman M, Shih I, Theodorescu D, Torbenson MS, Velculescu VE, Wang TL, Wentzensen N, Wood LD, Zhang M, McLendon RE, Bigner DD, Kinzler KW, Vogelstein B, Papadopoulos N, Yan H (2013). "TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal". Proc. Natl. Acad. Sci. U.S.A. 110 (15): 6021–6. doi:10.1073/pnas.1303607110. PMC 3625331. PMID 23530248. Vancouver style error: initials (help)
  4. ↑ Nault JC, Mallet M, Pilati C, Calderaro J, Bioulac-Sage P, Laurent C, Laurent A, Cherqui D, Balabaud C, Zucman-Rossi J, Zucman Rossi J (2013). "High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions". Nat Commun. 4: 2218. doi:10.1038/ncomms3218. PMC 3731665. PMID 23887712.
  5. ↑ Chen YL, Jeng YM, Chang CN, Lee HJ, Hsu HC, Lai PL, Yuan RH (2014). "TERT promoter mutation in resectable hepatocellular carcinomas: a strong association with hepatitis C infection and absence of hepatitis B infection". Int J Surg. 12 (7): 659–65. doi:10.1016/j.ijsu.2014.05.066. PMID 24866078.
  6. ↑ Schulze K, Imbeaud S, Letouzé E, Alexandrov LB, Calderaro J, Rebouissou S, Couchy G, Meiller C, Shinde J, Soysouvanh F, Calatayud AL, Pinyol R, Pelletier L, Balabaud C, Laurent A, Blanc JF, Mazzaferro V, Calvo F, Villanueva A, Nault JC, Bioulac-Sage P, Stratton MR, Llovet JM, Zucman-Rossi J (2015). "Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets". Nat. Genet. 47 (5): 505–511. doi:10.1038/ng.3252. PMC 4587544. PMID 25822088.
  7. ↑ Totoki Y, Tatsuno K, Covington KR, Ueda H, Creighton CJ, Kato M, Tsuji S, Donehower LA, Slagle BL, Nakamura H, Yamamoto S, Shinbrot E, Hama N, Lehmkuhl M, Hosoda F, Arai Y, Walker K, Dahdouli M, Gotoh K, Nagae G, Gingras MC, Muzny DM, Ojima H, Shimada K, Midorikawa Y, Goss JA, Cotton R, Hayashi A, Shibahara J, Ishikawa S, Guiteau J, Tanaka M, Urushidate T, Ohashi S, Okada N, Doddapaneni H, Wang M, Zhu Y, Dinh H, Okusaka T, Kokudo N, Kosuge T, Takayama T, Fukayama M, Gibbs RA, Wheeler DA, Aburatani H, Shibata T (2014). "Trans-ancestry mutational landscape of hepatocellular carcinoma genomes". Nat. Genet. 46 (12): 1267–73. doi:10.1038/ng.3126. PMID 25362482.
  8. ↑ Cleary SP, Jeck WR, Zhao X, Chen K, Selitsky SR, Savich GL, Tan TX, Wu MC, Getz G, Lawrence MS, Parker JS, Li J, Powers S, Kim H, Fischer S, Guindi M, Ghanekar A, Chiang DY (2013). "Identification of driver genes in hepatocellular carcinoma by exome sequencing". Hepatology. 58 (5): 1693–702. doi:10.1002/hep.26540. PMC 3830584. PMID 23728943.
  9. ↑ Hussain SP, Schwank J, Staib F, Wang XW, Harris CC (2007). "TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer". Oncogene. 26 (15): 2166–76. doi:10.1038/sj.onc.1210279. PMID 17401425.
  10. ↑ Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, Calderaro J, Bioulac-Sage P, Letexier M, Degos F, Clément B, Balabaud C, Chevet E, Laurent A, Couchy G, Letouzé E, Calvo F, Zucman-Rossi J (2012). "Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma". Nat. Genet. 44 (6): 694–8. doi:10.1038/ng.2256. PMC 3819251. PMID 22561517.
  11. ↑ Kan Z, Zheng H, Liu X, Li S, Barber TD, Gong Z, Gao H, Hao K, Willard MD, Xu J, Hauptschein R, Rejto PA, Fernandez J, Wang G, Zhang Q, Wang B, Chen R, Wang J, Lee NP, Zhou W, Lin Z, Peng Z, Yi K, Chen S, Li L, Fan X, Yang J, Ye R, Ju J, Wang K, Estrella H, Deng S, Wei P, Qiu M, Wulur IH, Liu J, Ehsani ME, Zhang C, Loboda A, Sung WK, Aggarwal A, Poon RT, Fan ST, Wang J, Hardwick J, Reinhard C, Dai H, Li Y, Luk JM, Mao M (2013). "Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma". Genome Res. 23 (9): 1422–33. doi:10.1101/gr.154492.113. PMC 3759719. PMID 23788652.
  12. ↑ Ozturk M (1991). "p53 mutation in hepatocellular carcinoma after aflatoxin exposure". Lancet. 338 (8779): 1356–9. PMID 1682737.
  13. ↑ Madden CR, Finegold MJ, Slagle BL (2002). "Altered DNA mutation spectrum in aflatoxin b1-treated transgenic mice that express the hepatitis B virus x protein". J. Virol. 76 (22): 11770–4. PMC 136763. PMID 12388740.
  14. ↑ Villanueva A, Llovet JM (2014). "Liver cancer in 2013: Mutational landscape of HCC--the end of the beginning". Nat Rev Clin Oncol. 11 (2): 73–4. doi:10.1038/nrclinonc.2013.243. PMID 24395088.
  15. ↑ Wang K, Lim HY, Shi S, Lee J, Deng S, Xie T, Zhu Z, Wang Y, Pocalyko D, Yang WJ, Rejto PA, Mao M, Park CK, Xu J (2013). "Genomic landscape of copy number aberrations enables the identification of oncogenic drivers in hepatocellular carcinoma". Hepatology. 58 (2): 706–17. doi:10.1002/hep.26402. PMID 23505090.
  16. ↑ Su PF, Lee TC, Lin PJ, Lee PH, Jeng YM, Chen CH, Liang JD, Chiou LL, Huang GT, Lee HS (2007). "Differential DNA methylation associated with hepatitis B virus infection in hepatocellular carcinoma". Int. J. Cancer. 121 (6): 1257–64. doi:10.1002/ijc.22849. PMID 17534893.
  17. ↑ Wong IH, Lo YM, Zhang J, Liew CT, Ng MH, Wong N, Lai PB, Lau WY, Hjelm NM, Johnson PJ (1999). "Detection of aberrant p16 methylation in the plasma and serum of liver cancer patients". Cancer Res. 59 (1): 71–3. PMID 9892188.
  18. ↑ Zhang YJ, Ahsan H, Chen Y, Lunn RM, Wang LY, Chen SY, Lee PH, Chen CJ, Santella RM (2002). "High frequency of promoter hypermethylation of RASSF1A and p16 and its relationship to aflatoxin B1-DNA adduct levels in human hepatocellular carcinoma". Mol. Carcinog. 35 (2): 85–92. doi:10.1002/mc.10076. PMID 12325038.
  19. ↑ Zhong S, Tang MW, Yeo W, Liu C, Lo YM, Johnson PJ (2002). "Silencing of GSTP1 gene by CpG island DNA hypermethylation in HBV-associated hepatocellular carcinomas". Clin. Cancer Res. 8 (4): 1087–92. PMID 11948118.
  20. ↑ Bakker J, Lin X, Nelson WG (2002). "Methyl-CpG binding domain protein 2 represses transcription from hypermethylated pi-class glutathione S-transferase gene promoters in hepatocellular carcinoma cells". J. Biol. Chem. 277 (25): 22573–80. doi:10.1074/jbc.M203009200. PMID 11960994.
  21. ↑ Niwa Y, Kanda H, Shikauchi Y, Saiura A, Matsubara K, Kitagawa T, Yamamoto J, Kubo T, Yoshikawa H (2005). "Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma". Oncogene. 24 (42): 6406–17. doi:10.1038/sj.onc.1208788. PMID 16007195.
  22. ↑ Zhang YJ, Chen Y, Ahsan H, Lunn RM, Lee PH, Chen CJ, Santella RM (2003). "Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation and its relationship to aflatoxin B1-DNA adducts and p53 mutation in hepatocellular carcinoma". Int. J. Cancer. 103 (4): 440–4. doi:10.1002/ijc.10852. PMID 12478658.
  23. ↑ Fujimoto A, Totoki Y, Abe T, Boroevich KA, Hosoda F, Nguyen HH, Aoki M, Hosono N, Kubo M, Miya F, Arai Y, Takahashi H, Shirakihara T, Nagasaki M, Shibuya T, Nakano K, Watanabe-Makino K, Tanaka H, Nakamura H, Kusuda J, Ojima H, Shimada K, Okusaka T, Ueno M, Shigekawa Y, Kawakami Y, Arihiro K, Ohdan H, Gotoh K, Ishikawa O, Ariizumi S, Yamamoto M, Yamada T, Chayama K, Kosuge T, Yamaue H, Kamatani N, Miyano S, Nakagama H, Nakamura Y, Tsunoda T, Shibata T, Nakagawa H (2012). "Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators". Nat. Genet. 44 (7): 760–4. doi:10.1038/ng.2291. PMID 22634756.
  24. ↑ 24.0 24.1 Li M, Zhao H, Zhang X, Wood LD, Anders RA, Choti MA, Pawlik TM, Daniel HD, Kannangai R, Offerhaus GJ, Velculescu VE, Wang L, Zhou S, Vogelstein B, Hruban RH, Papadopoulos N, Cai J, Torbenson MS, Kinzler KW (2011). "Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma". Nat. Genet. 43 (9): 828–9. doi:10.1038/ng.903. PMC 3163746. PMID 21822264.
  25. ↑ Xu J, Zhu X, Wu L, Yang R, Yang Z, Wang Q, Wu F (2012). "MicroRNA-122 suppresses cell proliferation and induces cell apoptosis in hepatocellular carcinoma by directly targeting Wnt/β-catenin pathway". Liver Int. 32 (5): 752–60. doi:10.1111/j.1478-3231.2011.02750.x. PMID 22276989.
  26. ↑ Tsai WC, Hsu PW, Lai TC, Chau GY, Lin CW, Chen CM, Lin CD, Liao YL, Wang JL, Chau YP, Hsu MT, Hsiao M, Huang HD, Tsou AP (2009). "MicroRNA-122, a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma". Hepatology. 49 (5): 1571–82. doi:10.1002/hep.22806. PMID 19296470.
  27. ↑ Fornari F, Gramantieri L, Giovannini C, Veronese A, Ferracin M, Sabbioni S, Calin GA, Grazi GL, Croce CM, Tavolari S, Chieco P, Negrini M, Bolondi L (2009). "MiR-122/cyclin G1 interaction modulates p53 activity and affects doxorubicin sensitivity of human hepatocarcinoma cells". Cancer Res. 69 (14): 5761–7. doi:10.1158/0008-5472.CAN-08-4797. PMID 19584283.
  28. ↑ Wang Y, Lee CG (2011). "Role of miR-224 in hepatocellular carcinoma: a tool for possible therapeutic intervention?". Epigenomics. 3 (2): 235–43. doi:10.2217/epi.11.5. PMID 22122284.
  29. ↑ Wang Y, Ren J, Gao Y, Ma JZ, Toh HC, Chow P, Chung AY, Ooi LL, Lee CG (2013). "MicroRNA-224 targets SMAD family member 4 to promote cell proliferation and negatively influence patient survival". PLoS ONE. 8 (7): e68744. doi:10.1371/journal.pone.0068744. PMC 3726696. PMID 23922662.
  30. ↑ Sun J, Lu H, Wang X, Jin H (2013). "MicroRNAs in hepatocellular carcinoma: regulation, function, and clinical implications". ScientificWorldJournal. 2013: 924206. doi:10.1155/2013/924206. PMC 3575633. PMID 23431261.
  31. ↑ Du Y, Kong G, You X, Zhang S, Zhang T, Gao Y, Ye L, Zhang X (2012). "Elevation of highly up-regulated in liver cancer (HULC) by hepatitis B virus X protein promotes hepatoma cell proliferation via down-regulating p18". J. Biol. Chem. 287 (31): 26302–11. doi:10.1074/jbc.M112.342113. PMC 3406714. PMID 22685290.
  32. ↑ Xie H, Ma H, Zhou D (2013). "Plasma HULC as a promising novel biomarker for the detection of hepatocellular carcinoma". Biomed Res Int. 2013: 136106. doi:10.1155/2013/136106. PMC 3674644. PMID 23762823.
  33. ↑ Yang F, Zhang L, Huo XS, Yuan JH, Xu D, Yuan SX, Zhu N, Zhou WP, Yang GS, Wang YZ, Shang JL, Gao CF, Zhang FR, Wang F, Sun SH (2011). "Long noncoding RNA high expression in hepatocellular carcinoma facilitates tumor growth through enhancer of zeste homolog 2 in humans". Hepatology. 54 (5): 1679–89. doi:10.1002/hep.24563. PMID 21769904.
  34. ↑ Huang JF, Guo YJ, Zhao CX, Yuan SX, Wang Y, Tang GN, Zhou WP, Sun SH (2013). "Hepatitis B virus X protein (HBx)-related long noncoding RNA (lncRNA) down-regulated expression by HBx (Dreh) inhibits hepatocellular carcinoma metastasis by targeting the intermediate filament protein vimentin". Hepatology. 57 (5): 1882–92. doi:10.1002/hep.26195. PMID 23239537.
  35. ↑ Yuan SX, Yang F, Yang Y, Tao QF, Zhang J, Huang G, Yang Y, Wang RY, Yang S, Huo XS, Zhang L, Wang F, Sun SH, Zhou WP (2012). "Long noncoding RNA associated with microvascular invasion in hepatocellular carcinoma promotes angiogenesis and serves as a predictor for hepatocellular carcinoma patients' poor recurrence-free survival after hepatectomy". Hepatology. 56 (6): 2231–41. doi:10.1002/hep.25895. PMID 22706893.
  36. ↑ Lay AJ, Jiang XM, Kisker O, Flynn E, Underwood A, Condron R, Hogg PJ (2000). "Phosphoglycerate kinase acts in tumour angiogenesis as a disulphide reductase". Nature. 408 (6814): 869–73. doi:10.1038/35048596. PMID 11130727.
  37. ↑ Yang Z, Zhou L, Wu LM, Lai MC, Xie HY, Zhang F, Zheng SS (2011). "Overexpression of long non-coding RNA HOTAIR predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation". Ann. Surg. Oncol. 18 (5): 1243–50. doi:10.1245/s10434-011-1581-y. PMID 21327457.
  38. ↑ Geng YJ, Xie SL, Li Q, Ma J, Wang GY (2011). "Large intervening non-coding RNA HOTAIR is associated with hepatocellular carcinoma progression". J. Int. Med. Res. 39 (6): 2119–28. doi:10.1177/147323001103900608. PMID 22289527.
  39. ↑ Li G, Zhang H, Wan X, Yang X, Zhu C, Wang A, He L, Miao R, Chen S, Zhao H (2014). "Long noncoding RNA plays a key role in metastasis and prognosis of hepatocellular carcinoma". Biomed Res Int. 2014: 780521. doi:10.1155/2014/780521. PMC 3976793. PMID 24757675.
  40. ↑ Lau CC, Sun T, Ching AK, He M, Li JW, Wong AM, Co NN, Chan AW, Li PS, Lung RW, Tong JH, Lai PB, Chan HL, To KF, Chan TF, Wong N (2014). "Viral-human chimeric transcript predisposes risk to liver cancer development and progression". Cancer Cell. 25 (3): 335–49. doi:10.1016/j.ccr.2014.01.030. PMID 24582836.
  41. ↑ Thompson MD, Monga SP (2007). "WNT/beta-catenin signaling in liver health and disease". Hepatology. 45 (5): 1298–305. doi:10.1002/hep.21651. PMID 17464972.
  42. ↑ Hoshida Y, Nijman SM, Kobayashi M, Chan JA, Brunet JP, Chiang DY, Villanueva A, Newell P, Ikeda K, Hashimoto M, Watanabe G, Gabriel S, Friedman SL, Kumada H, Llovet JM, Golub TR (2009). "Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma". Cancer Res. 69 (18): 7385–92. doi:10.1158/0008-5472.CAN-09-1089. PMC 3549578. PMID 19723656.
  43. ↑ Tanabe KK, Lemoine A, Finkelstein DM, Kawasaki H, Fujii T, Chung RT, Lauwers GY, Kulu Y, Muzikansky A, Kuruppu D, Lanuti M, Goodwin JM, Azoulay D, Fuchs BC (2008). "Epidermal growth factor gene functional polymorphism and the risk of hepatocellular carcinoma in patients with cirrhosis". JAMA. 299 (1): 53–60. doi:10.1001/jama.2007.65. PMID 18167406.
  44. ↑ Kaposi-Novak P, Lee JS, Gòmez-Quiroz L, Coulouarn C, Factor VM, Thorgeirsson SS (2006). "Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype". J. Clin. Invest. 116 (6): 1582–95. doi:10.1172/JCI27236. PMC 1462944. PMID 16710476.
  45. ↑ Llovet JM, Peña CE, Lathia CD, Shan M, Meinhardt G, Bruix J (2012). "Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma". Clin. Cancer Res. 18 (8): 2290–300. doi:10.1158/1078-0432.CCR-11-2175. PMID 22374331.
  46. ↑ French DM, Lin BC, Wang M, Adams C, Shek T, Hötzel K, Bolon B, Ferrando R, Blackmore C, Schroeder K, Rodriguez LA, Hristopoulos M, Venook R, Ashkenazi A, Desnoyers LR (2012). "Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models". PLoS ONE. 7 (5): e36713. doi:10.1371/journal.pone.0036713. PMC 3352934. PMID 22615798.
  47. ↑ Desnoyers LR, Pai R, Ferrando RE, Hötzel K, Le T, Ross J, Carano R, D'Souza A, Qing J, Mohtashemi I, Ashkenazi A, French DM (2008). "Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models". Oncogene. 27 (1): 85–97. doi:10.1038/sj.onc.1210623. PMID 17599042.
  48. ↑ Yoshiji H, Kuriyama S, Noguchi R, Yoshii J, Ikenaka Y, Yanase K, Namisaki T, Kitade M, Uemura M, Masaki T, Fukui H (2005). "Angiopoietin 2 displays a vascular endothelial growth factor dependent synergistic effect in hepatocellular carcinoma development in mice". Gut. 54 (12): 1768–75. doi:10.1136/gut.2005.067900. PMC 1774778. PMID 16033879.
  49. ↑ Park YN, Kim YB, Yang KM, Park C (2000). "Increased expression of vascular endothelial growth factor and angiogenesis in the early stage of multistep hepatocarcinogenesis". Arch. Pathol. Lab. Med. 124 (7): 1061–5. doi:10.1043/0003-9985(2000)124<1061:IEOVEG>2.0.CO;2. PMID 10888784.
  50. ↑ Kim KW, Bae SK, Lee OH, Bae MH, Lee MJ, Park BC (1998). "Insulin-like growth factor II induced by hypoxia may contribute to angiogenesis of human hepatocellular carcinoma". Cancer Res. 58 (2): 348–51. PMID 9443416.
  51. ↑ Cannito S, Turato C, Paternostro C, Biasiolo A, Colombatto S, Cambieri I, Quarta S, Novo E, Morello E, Villano G, Fasolato S, Musso T, David E, Tusa I, Rovida E, Autelli R, Smedile A, Cillo U, Pontisso P, Parola M (2015). "Hypoxia up-regulates SERPINB3 through HIF-2α in human liver cancer cells". Oncotarget. 6 (4): 2206–21. doi:10.18632/oncotarget.2943. PMC 4385846. PMID 25544768.
  52. ↑ Luo D, Wang Z, Wu J, Jiang C, Wu J (2014). "The role of hypoxia inducible factor-1 in hepatocellular carcinoma". Biomed Res Int. 2014: 409272. doi:10.1155/2014/409272. PMC 4101982. PMID 25101278.
  53. ↑ Coulouarn C, Factor VM, Thorgeirsson SS (2008). "Transforming growth factor-beta gene expression signature in mouse hepatocytes predicts clinical outcome in human cancer". Hepatology. 47 (6): 2059–67. doi:10.1002/hep.22283. PMC 2762280. PMID 18506891.
  54. ↑ Giannelli G, Bergamini C, Fransvea E, Sgarra C, Antonaci S (2005). "Laminin-5 with transforming growth factor-beta1 induces epithelial to mesenchymal transition in hepatocellular carcinoma". Gastroenterology. 129 (5): 1375–83. doi:10.1053/j.gastro.2005.09.055. PMID 16285938.
  55. ↑ Reynolds AR, Furlan A, Fetzer DT, Sasatomi E, Borhani AA, Heller MT, Tublin ME (2015). "Infiltrative hepatocellular carcinoma: what radiologists need to know". Radiographics. 35 (2): 371–86. doi:10.1148/rg.352140114. PMID 25763723.
  56. ↑ "Hepatocellular carcinoma".


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