Novel strategies for hepatocellular carcinoma based on MMPs science.

Anticancer Agents Med Chem. 2012 Sep;12(7):753-63.

Isao Okazaki1* and Yutaka Inagaki2


1Department of Internal Medicine, Sanno Hospital and University Hospital, International University of Health and Welfare, Tokyo and Tochigi Prefecture, and 2Department of Regenerative Medicine, Tokai University School of Medicine, Isehara, Kanagawa Prefecture, Japan



Background: Hepatocellular carcinoma (HCC) is a cancer with extremely poor prognosis, and the third leading cause of cancer-related mortality in the world, responsible for more than 600,000 deaths annualy. Epidemiological studies have revealed that 50% to 80% of HCC cases are related to hepatitis B virus (HBV) infection, and 10% to 25% are thought to be the result of hepatitis C virus (HCV) infection. The authors reviewed recent reports on in situ hybridization to detect mRNAs of both MMPs including ADAMs/ADAMTSs and TIMPs and immunohistochemical localization of their proteins as well as mechanism of cancer invasion with/without metastasis from MMPs science because no review on this problems has been reported, and proposed a novel strategies for HCC treatment.

Pathological Characterization of HCC : A nodule of early HCC smaller than 2 cm in diameter is composed of well-differentiated and moderately differentiated cancer cells. Portal tracts and fibrotic septa of cirrhosis remain within the nodule of early HCC. These structures disappear gradually as the nodule grows in size. This disappearance seems to be correlated with stromal invasion by well-differentiated cancer cells. Well-differentiated cancer cells are thought to destroy fibrous tissue such as portal tracts and fibrous bands in cirrhotic liver.

Localization of MMPs and TIMPS in HCC : A conversion from adenomatous hyperplasia to atypical adenomatous hyperplasia within liver cirrhosis obtains a phenotype to express MMP-1, resulting in the formation of a new clone. Several well-differentiated hepatoma cells express MT1-MMP and gradually small amounts of MMP-2 and MMP-9, probably stimulated by inflammatory cytokines or TGF-b. MMP-1-positive clones are compressed by new clones and subsequently disappear. Positive cells for MMP-2 and MMP-9 may participate in the degradation of the fibrous tissue to make hepatoma cells easily invade or to form the thick capsule around the nodule as shown in Figure.

Regulatory Mechanism of MMPs and TIMPs in HCC : Overexpressing p28GANK and Fascin-1 are involved in epithelial-mesenchymal transition (EMT) and increase in invasiveness and angiogenesis. p28GANK is an oncoprotein, and up-regulation of p28GANK correlates with cell cycle progression in hepatocytes. The p28GANK activates PI3K/akt/HIF1αto promote TWIST1, VEGF and MMP-2 expression. Fascin-1 is thought to act as a migration factor associated with EMT in HCC and to facilitate the invasiveness in combination with MMPs.

Anti-cancer Agents for HCC and Their Regulatory Mechanism : Translation

al research studies on anti-cancer agents are introduced.

Future-oriented Strategies Based on MMPs Science: The JNK pathway is involved in constitutive MMP-1 expression only in well-differentiated HCC but not in less differentiated HCC. A novel strategy has to be developed for preventing the occurrence of well-differentiated hepatoma cells or MMP-1-positive cancer cells. We need to clarify whether MMP-1-positive cancer cells are cancer stem cells among well-differentiated hepatoma cells in the early stages of HCC, and whether budding of cancer stem cells are present in atypical adenomatous hyperplasia and adenomatous hyperplasia that exhibit JNK activation and MMP-1 mRNA expression. The JNK inhibitor agent should be studied in vivo and the expression of MMP-1 mRNA and CD133 should be investigated as target markers in early HCC including atypical adenomatous hyperplasia.

PMID: 22292750

Isao Okazaki-1




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