Do the tumor cells of hepatocellular carcinomas dislodge into the portal venous stream during hepatic resection?

Yamanaka, Naoaki; Okamoto, Eizo; Fujihara, Shiro; Kato, Toshihiro; Fujimoto, Jiro; Oriyama, Takeshi; Mitsunobu, Masao; Toyosaka, Akihiro; Uematsu, Kazuyoshi; Yamamoto, Kakushi

doi:10.1002/1097-0142(19921101)70:9<2263::aid-cncr2820700909>3.0.co;2-m

Cited by 107 publications

(77 citation statements)

References 12 publications

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“…Indeed, dissemination of cancer cells from primary HCC into the portal vein during surgical resection has been observed. 20 Nevertheless, disseminated cells do not always survive in the circulation and form metastatic sites, although anchorage-independent growth and rapid growth of cancer cells after surgical resection may be important factors for early [21][22][23][24][25][26] such as tumor volume, histopathologic dedifferentiation, microscopic invasiveness, high cellular proliferation, and p53 mutation. A high serum concentration of ␣-fetoprotein, which reflects tumor volume, was reported to be a predictor of early disease recurrence, and a previous report showed that p53 mutation was associated with the progression of HCC as a late event in hepatocarcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Akt phosphorylation is a risk factor for early disease recurrence and poor prognosis in hepatocellular carcinoma

Nakanishi¹,

Sakamoto

Yamasaki

et al. 2005

Cancer

211

173

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BACKGROUND Patients with hepatocellular carcinoma (HCC) who showed early massive disease recurrence due to hematogenous intrahepatic metastasis after curative resection had a poor prognosis. The authors previously reported that Akt phosphorylation was correlated with hematogenous intrahepatic metastasis, using HCC cell lines. METHODS The authors analyzed clinicopathologic features and the status of selected biologic markers, including phosphorylated Akt, to identify risk factors for early disease recurrence and poor prognosis in HCC. In the current series, 49 postoperative patients developed intrahepatic disease recurrence within 6 months (Group 1) and 86 patients remained disease recurrence free > 3 years after resection (Group 2). Group 1 was further divided into 2 subgroups: 19 patients who died of disease recurrence within a year after resection (Group 1A) and 27 patients who survived > 1 year (Group 1B). RESULTS Using univariate analysis, the risk factors for early disease recurrence were tumor size, macroscopic classification, tumor differentiation, microscopic capsule infiltration, microscopic portal vein (MPV) invasion, microscopic intrahepatic metastasis (MIM), and positive immunostaining for phosphorylated Akt, Ki‐67, and p53 (P < 0.05). The risk factors for poor prognosis were the number of intrahepatic metastases, tumor differentiation, and positive immunostaining for phosphorylated Akt and Ki‐67 (P < 0.05). Multivariate analysis revealed that the risk factors for early disease recurrence were MPV invasion, MIM, and positive immunostaining for phosphorylated Akt, and that the risk factors for poor prognosis were positive immunostaining for phosphorylated Akt and Ki‐67 (P < 0.05). CONCLUSIONS The current clinical study showed the critical involvement of Akt phosphorylation in the aggressiveness of HCC. The potential benefits of surgery should be assessed carefully in patients with any of these risk factors. Cancer 2005. © 2004 American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

Akt phosphorylation is a risk factor for early disease recurrence and poor prognosis in hepatocellular carcinoma

Nakanishi¹,

Sakamoto

Yamasaki

et al. 2005

Cancer

211

173

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“…were as follows: 72.9% and 83.3% at 1 year; 58.3% and 83.3% liver. [7][8][9] However, recurrence is not rare even in cases with at 2 years, respectively (P õ .05) (Fig. 5).…”

Section: Methodsmentioning

confidence: 99%

Expression of urokinase-type plasminogen activator receptor in hepatocellular carcinoma

et al. 1997

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hepatic metastasis in their resected liver have shown recurIt is well known that a urokinase-type plasminogen rence within 3 years, 9 prompting us to seek a new predictor activator receptor (uPAR) is a key protein in the plasfor this recurrence. minogen activation system, which plays a proteolyti-The metastatic process in malignant tumors involves local cally important role in the invasion and metastasis of invasion, intravasation, and extravasation. 10 These events various cancer cells. To assess the expression of uPAR depend on the tumor-associated proteolytic process including in hepatocellular carcinoma (HCC), we analyzed the exthe plasminogen activation system, and many reports have pression of uPAR messenger RNA (mRNA) and the proshown that the urokinase-type plasminogen activator (uPA) tein in 31 pair-samples of solitary HCC and nontumorous plays an important role in this process. 11-13 uPA is released liver tissues from the same patients. Fifteen samples exfrom tumor and stromal cells [14][15][16] in a single-chain zymogen hibited no histological potential of recurrence, such as form, pro-uPA. 17,18 pro-uPA is converted into a two-chain acportal involvement or intrahepatic metastasis (group A), tive form of uPA, which converts the ubiquitous zymogen and 16 samples exhibited such histological features plasminogen into the proteolytically active form, plasmin. (group B). Seventy-one percent of the cases showedPlasmin by itself degrades the extracellular matrix and actiuPAR signals, and these signals were mainly localized vates collagenases. 19 Some authors have described that poor at the cytoplasm of the tumor cells and tended to be at prognostic types of cancer cells show high levels of uPA. 20-22the front of invasive foci. 87.5% of the cases in group B The mechanism of the initial activation of pro-uPA under showed uPAR signals against 53.3% of the cases in group physiological conditions is unknown. uPA has a specific re-A (P õ .05). The rate of recurrence in the uPAR positive/ ceptor (uPAR) anchoring to the cell surface by glycosyl-phonegative cases in group A was 75.0% and 14.3%, respecphatidyl-inositol. [23][24][25][26][27] uPAR is a protein with an Mr55000-tively (P õ .05). In non-neoplastic cases, e.g., chronic ac-60000 (55-60 Kd molecular weight of uPAR antigen), tive hepatitis and cirrhosis, weak uPAR mRNA and protranslated from a 1.4-kb messenger RNA (mRNA) 28 and its tein signals were detected in hepatocytes neighboring amino-terminal domain has a high affinity with an epidermal the portal tracts, suggesting that this protein plays some growth factor-like domain in the pro-uPA and uPA molerole in such cases. The present study indicates that cules. 29,30 uPAR synthesis is regulated by growth factors such uPAR plays an important role at least in its initial stage as transforming growth factors b 1 and b 2 , epidermal growth in invasion and metastasis of HCC, and that uPAR exfactor, 31,32 and phorbol 12-myristate 13-acetate. 33 Binding of pression can be a candidate predictor of these factors.pro...

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“…28,29 IM is thought to develop through tumor cell dissemination through the portal vein. 30 Previous studies using the mouse IM model indicate activation of RhoA 21 and AKT, 31 and overexpression of cortactin 32 Reduced TGFBR2 expression correlated with portal vain invasion in HCC cases, and poorly differentiated HCC cells showed lower TGFBR2 expression compared with well-differentiated cells. This suggests that HCC cells, with reduced TGFBR2 expression, seem to be more invasive and may promote IM.…”

Section: Tgfbr2 Expression In Hccsmentioning

confidence: 99%

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

Mamiya

Yamazaki

Masugi

et al. 2010

Laboratory Investigation

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Hepatocellular carcinoma (HCC) occurs mainly in the liver associated with chronic hepatitis and hepatic cirrhosis as a result of prolonged viral infection. Transforming growth factor-b (TGF-b) induces the fibrosis in hepatic cirrhosis, although it is also an inhibitor of hepatocyte proliferation. To understand the role of TGF-b signaling in HCC progression, we analyzed gene expression in HCC cells in relation to TGF-b signaling using a two-way clustering algorithm. By the analysis, five HCC cell lines were classified into two groups according to their metastatic capacity. TGF-b receptor II (TGFBR2) was downregulated in metastatic cells, which did not show a response to TGF-b. Immunohistochemistry demonstrated clear membrane distribution of TGFBR2 in noncancerous hepatocytes, whereas reduced TGFBR2 expression was observed in 34 of 136 HCCs. In clinical cases, reduced TGFBR2 expression correlated with larger tumor size (Po0.001), poor differentiation (Po0.001), portal vein invasion (P ¼ 0.002), intrahepatic metastasis (IM) (Po0.001), and shorter recurrence-free survival (P ¼ 0.022). In conclusion, reduced TGFBR2 expression was associated with aggressive features of HCC such as IM, and may represent an immunohistochemical biomarker to detect aggressive HCC. Hepatocellular carcinoma (HCC) is a common cause of death from cancer worldwide. 1 Prolonged infection with hepatitis virus often causes chronic hepatitis, followed by liver cirrhosis. 2 During the development of these liver diseases, transforming growth factor-b (TGF-b) has an important role in fibrosis of the lesions. 3 HCCs mainly occur in those injured livers with activated TGF-b signaling, although TGF-b inhibits hepatocyte cell growth in the normal liver. 4,5 TGF-b signaling is activated when a TGF-b ligand binds to its receptor on the cell membrane. The downstream effectors, SMAD2 and SMAD3, together with SMAD4, translocate to the nucleus and regulate the expression of various genes, including cyclin-dependent kinase inhibitor 1A (CDKN1A), which is involved in cell growth arrest. 6,7 TGF-b signaling is also suggested to be involved in the malignant progression of tumors. TGF-b can induce epithelial-mesenchymal transition and promote tumor cell invasion, and may also have angiogenic and immunosuppressive effects on the tumor microenvironment, all of which promote metastasis. 8 Mutations in the TGF-b superfamily genes have been found in various cancers. The TGF-b receptor II (TGFBR2) gene is frequently mutated in colon cancers, 9,10 gastric cancers, 10,11 and in gliomas 12 with microsatellite instability. SMAD4 mutations occur mainly in pancreatic cancers, in which the SMAD4 gene was first identified as a tumorsuppressor gene. 13 In HCCs, however, mutations in TGF-b superfamily genes are rare, 14,15 and alteration of TGF-b signaling is still unclear and controversial. To investigate alterations of TGF-b signaling in HCC progression, we compared the expression profiles of TGF-b signalingrelated genes in HCC cells exhibiting different metastatic potential. We...

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Do the tumor cells of hepatocellular carcinomas dislodge into the portal venous stream during hepatic resection?

Cited by 107 publications

References 12 publications

Akt phosphorylation is a risk factor for early disease recurrence and poor prognosis in hepatocellular carcinoma

Akt phosphorylation is a risk factor for early disease recurrence and poor prognosis in hepatocellular carcinoma

Expression of urokinase-type plasminogen activator receptor in hepatocellular carcinoma

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

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