Cell motility mediated by rho and rho-associated protein kinase plays a critical role in intrahepatic metastasis of human hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common and aggressive malignancies in the world. Recent advances in diagnostic modalities, such as imaging techniques and measurement of serum tumor markers, have improved the rate of early detection of HCC, and therapeutic approaches to HCC have also progressed. However, the long-term survival of HCC patients has been poor because of the high incidence of recurrence within the liver after initial treatment. 1,2 Pathological and genetic studies have identified two types of recurrence of HCC: multicentric development of new tumors 3-5 and intrahepatic metastasis of the original HCC.Intrahepatic metastasis of HCC is frequently observed with the advance of the disease and it is thought to develop through tumor cell dispersal via the portal vein. 6 A clinicopathological study showed that intrahepatic metastatic tumors develop more frequently in cases of HCC with a replacing or infiltrative growth component than in cases without such a component. 7 Proliferating cell nuclear antigen expression by HCCs seems to be related to tumor invasiveness and the prognosis, 8,9 and the nuclear DNA content of the tumor cells correlates with the postoperative recurrence of HCC. 10 Several chromosomal alterations appear to be responsible for the development of human HCC, 11,12 especially loss of heterozygosity of chromosome 16, which is detected at a higher rate in HCCs with intrahepatic metastasis and portal vein tumor thrombi. 13 Furthermore, E-cadherin expression seems to be involved in secondary tumor formation by HCC cells in the liver. 14 However, the molecular and cellular mechanisms underlying intrahepatic metastasis of HCC are not fully understood.Cancer metastasis is a multistep process that involves cell detachment from the primary tumor, entry into the vascular or lymphatic system, dispersal through the circulation, and extravasation and proliferation in the target organ. Metastatic cancer cells are equipped with properties that help them complete each step of this process. 15 In case of intrahepatic metastasis of human HCC, the dispersed cancer cells proliferate in the same environment as the primary lesion. Therefore, the initial step, including detachment of the cancer cells from the primary lesion, may offer the best chance to regulate metastatic ability.In this study, to clarify the molecular and cellular mechanisms underlying intrahepatic metastasis of human HCC, we have developed a model of intrahepatic metastasis using orthotopic implantation of human HCC cell lines in SCID Abbreviations: HCC, hepatocellular carcinoma; GTPase, guanosine triphosphatase; p160ROCK, Rho-associated coiled-coil forming protein kinase; LPA, lysophosphatidic acid.From the

Reduced transforming growth factor-β receptor II expression in hepatocellular carcinoma correlates with intrahepatic metastasis

“…These cells have been previously classified into two groups on the basis of metastatic potential in a mouse intrahepatic metastasis (IM) model, in which orthotopically implanted KYN-2 and Li7 cells formed secondary foci in the mouse liver, whereas others did not. 21 Thus, the classification by the clustering analysis in this study reflected the classification based on metastatic potential in the mouse model. In the central transducers of TGF-b signaling pathway (ligands-receptors-SMADs), TGFBR2 showed markedly different expression between the two groups.…”

Platycodin D Induces Apoptosis, and Inhibits Adhesion, Migration and Invasion in HepG2 Hepatocellular Carcinoma Cells

“…To reduce the metastasis could be a promising stratagem for treatment of hepatocellular carcinoma, as the poor prognosis of hepatocellular carcinoma is largely due to a high rate of metastasis (Genda et al, 1999;Ye et al, 2003). Metastasis of cancer cells includes several steps while change of cell-cell and cell-extracellular matrix (ECM) adhesion capacity is the initial step in this process.…”

Amplification of MPZL1/PZR promotes tumor cell migration through Src-mediated phosphorylation of cortactin in hepatocellular carcinoma

“…The results showed that different expression levels of the MPZL1 gene can be detected in all the six HCC cell lines ( Figure 3A). Specifically, the protein level of MPZL1 was relatively low in HepG2, Hep3B, HUH-7 and SMMC-7721 cells, which have no or low metastatic potential [4,[23][24][25], whereas the protein level of the MPZL1 gene was relatively high in SK-HEP-1 and Li-7 cells, which have high metastatic potential [24,26].…”