Cell cycle biology of fibrolamellar hepatocellular carcinoma.

CONTEXT fibrolamellar hepatocellular carcinoma (FLHCC) has a better prognosis than conventional hepatocellular carcinoma. Nevertheless, FLHCC has a propensity to recur with limited responsiveness to chemotherapy. OBJECTIVE The purpose of this study was to provide insight into the cell cycle biology of FLHCC, as it relates to FLHCC's relatively indolent nature and lack of chemoresponsiveness. DESIGN in seven cases of FLHCC, we assessed: 1. immunoexpression of protein analytes indicating cell cycle progression including Ki-67 (G1, S, G2 and M phases) and S-phase kinase-associated protein (Skp) 2 along with the mitotic index (MI); 2.immunoreactivity for cyclin-dependent kinase inhibitors of cell cycle progression from G1 to S phase, p27Kip1 and p16INK4. RESULTS the mean percentage of Ki-67 nuclear positivity in neoplastic hepatocytes ranged from 1.0% to 29.7%. Nuclear Skp2 immunoexpression was not observed in any of the cases. The mitotic index was very low (0-1 mitotic figure / 10 high-power fields). All cases showed moderate to strong nuclear p16INK4 positivity (diffuse in five and focal in two). Contras-tively, the adjacent non-neoplastic hepatocytes expressed only mild (2 cases) to no (3 cases) p16INK4. CONCLUSION our analysis has revealed that cell cycle arrest in FLHCC occurs in G0G1 phase and is associated with overexpression of the cell cycle regulator, p16INK4 in tumoral cell nuclei compared with non-neoplastic hepatocytes. In conjunction with our previous immunohistochemical demonstration of a constitutively activated nuclear factor (NF)-kappaB pathway and stemness characteristics of FLHCC with limited differentiation, this cell cycle arrest elucidates the biology of FLHCC's indolent nature and relative chemoresistance.

[1]  M. Speicher,et al.  Alterations of the cell-cycle inhibitors p27(KIP1) and p16(INK4a) are frequent in blastic plasmacytoid dendritic cell neoplasms. , 2010, The Journal of investigative dermatology.

[2]  Robert E. Brown,et al.  Stemness characteristics of fibrolamellar hepatocellular carcinoma: immunohistochemical analysis with comparisons to conventional hepatocellular carcinoma. , 2010, Annals of clinical and laboratory science.

[3]  Wei Li,et al.  Constitutive activation of nuclear factor-kappa B (NF-kB) signaling pathway in fibrolamellar hepatocellular carcinoma. , 2010, International journal of clinical and experimental pathology.

[4]  Shu Liu,et al.  Fibrolamellar Hepatocellular Carcinoma , 2009, The American Journal of Gastroenterology.

[5]  M. Barbacid,et al.  Cell cycle, CDKs and cancer: a changing paradigm , 2009, Nature Reviews Cancer.

[6]  S. Kakar,et al.  Chromosomal changes in fibrolamellar hepatocellular carcinoma detected by array comparative genomic hybridization , 2009, Modern Pathology.

[7]  J. Persson,et al.  Cancer therapy: targeting cell cycle regulators. , 2008, Anti-cancer agents in medicinal chemistry.

[8]  M. Torbenson,et al.  Epigenetic instability is rare in fibrolamellar carcinomas but common in viral-associated hepatocellular carcinomas , 2008, Modern Pathology.

[9]  Y. Matsuda.  Molecular mechanism underlying the functional loss of cyclindependent kinase inhibitors p16 and p27 in hepatocellular carcinoma. , 2008, World journal of gastroenterology.

[10]  M. Torbenson.  Review of the Clinicopathologic Features of Fibrolamellar Carcinoma , 2007, Advances in anatomic pathology.

[11]  T. Ichida,et al.  p16 and p27 are functionally correlated during the progress of hepatocarcinogenesis , 2006, Medical Molecular Morphology.

[12]  L. Terracciano,et al.  Fibrolamellar hepatocellular carcinoma occurring 5 years after hepatocellular adenoma in a 14-year-old girl: a case report with comparative genomic hybridization analysis. , 2004, Archives of pathology & laboratory medicine.

[13]  K. Vermeulen,et al.  The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer , 2003, Cell proliferation.

[14]  M. Pagano,et al.  S-phase kinase-associated protein 2 expression in non-Hodgkin's lymphoma inversely correlates with p27 expression and defines cells in S phase. , 2002, The American journal of pathology.

[15]  J. Pellegrin,et al.  Mécanismes moléculaires contrôlant le cycle cellulaire : aspects fondamentaux et implications en cancérologie , 2001 .

[16]  F. Lacombe,et al.  [Molecular mechanisms controlling the cell cycle: fundamental aspects and implications for oncology]. , 2001, Cancer radiotherapie : journal de la Societe francaise de radiotherapie oncologique.

[17]  J. Klempnauer,et al.  Cytogenetic aberrations in primary and recurrent fibrolamellar hepatocellular carcinoma detected by comparative genomic hybridization. , 2000, American Journal of Clinical Pathology.

[18]  P. Pineau,et al.  Distinct chromosomal abnormality pattern in primary liver cancer of non-B, non-C patients , 2000, Oncogene.

[19]  Hoguen Kim,et al.  p16 is a major inactivation target in hepatocellular carcinoma , 2000, Cancer.

[20]  H. Asakura,et al.  p16INK4 is inactivated by extensive CpG methylation in human hepatocellular carcinoma , 1999 .

[21]  M. Makuuchi,et al.  Molecular basis of multistep hepatocarcinogenesis: genetic and epigenetic events. , 1999, Scandinavian journal of gastroenterology.

[22]  H. Asakura,et al.  p16(INK4) is inactivated by extensive CpG methylation in human hepatocellular carcinoma. , 1999, Gastroenterology.

[23]  M. Makuuchi,et al.  Cell cycle regulators and human hepatocarcinogenesis. , 1998, Hepato-gastroenterology.

[24]  A. Kamb.  Cyclin-dependent kinase inhibitors and human cancer. , 1998, Current topics in microbiology and immunology.

[25]  F. Bosman,et al.  Germ‐line mutations of the p16INK4(MTS1) gene occur in a subset of patients with hepatocellular carcinoma , 1997, Hepatology.

[26]  B. Leggett,et al.  Frequency of mutation and deletion of the tumor suppressor gene CDKN2A (MTS1/p16) in hepatocellular carcinoma from an Australian population , 1997, Hepatology.

[27]  G. Peters,et al.  Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer. , 1996, Advances in cancer research.