[Show abstract][Hide abstract] ABSTRACT: Gastrinoma is most commonly located in the gastrinoma triangle (comprising of the duodenum, pancreas and bile ducts) or in the adjacent lymph nodes. Due to the low mortality rate, it is often misdiagnosed as other diseases with similar clinical characteristics, such as a solid pseudopapillary tumor of the pancreas (SPTP). Therefore, the current study reports a rare case of gastrinoma located in the tail of the pancreas of a female patient under medical examination, who exhibited no clinical symptoms. The tumor, which was located in the body and tail of the pancreas, was successfully resected and the spleen was preserved. The outcome of surgery combined with the postoperative pathological examination resulted in the patient being misdiagnosed with a SPTP. During the consequent six-year follow-up period, low-density liver lesions and an intractable peptic ulcer gradually appeared. Finally, the patient diagnosis was confirmed as a malignant pancreatic neuroendocrine carcinoma with liver metastases. On June 1, 2011, a liver transplant was successfully performed and the patient has maintained a good overall condition. The underlying clinical and pathological factors that may have resulted in misdiagnosis are investigated in the present study. Through providing our preliminary clinical experiences and lessons, the aim of the present study was to focus the attention of clinicians on this type of cancer in order to improve its diagnosis and treatment.
[Show abstract][Hide abstract] ABSTRACT: HOXA13 is a member of homeobox genes that encode transcription factors regulating embryonic development and cell fate. Abnormal HOXA13 expression was reported in hepatocellular carcinoma (HCC), but its correlation with tumor angiogenesis and prognosis still remain unclear. This study was aimed to uncover the expression, diagnostic and prognostic significance of HOXA13 in HCC. Immunohistochemistry was performed to detect HOXA13 expression in HCC and corresponding paracarcinomatous tissues from 90 patients. Enzyme-linked immunosorbent assay was used to detect serum HOXA13 in 90 HCC patients and 20 healthy volunteers. Receiver operating characteristics was analyzed to calculate diagnostic accuracy of serum HOXA13, alpha-fetoprotein (AFP) and their combination. Immunoreactivity of HOXA13 was detected in 72.2% of HCC, and 12.2% of adjacent non-cancerous samples. HOXA13 expression was significantly associated with tumor size, microvascular invasion, pathological grade, tumor capsula status, AFP level, tumor-node-metastasis stage and positively correlated with VEGF (p < 0.001) and microvessel density (p < 0.001). The combination of serum HOXA13 and AFP had a markedly higher area under the curve than HOXA13 alone. HOXA13 expression was associated with unfavorable overall survival (OS) (p < 0.001) and disease-free survival (DFS) (p < 0.001). Multivariate analysis indicated that patients with HOXA13-expressing tumors had a significantly shorter OS (p = 0.030) and DFS (p = 0.005) than those with HOXA13-negative tumors. Thus, HOXA13 expression possibly plays an important role in tumor angiogenesis, progression and prognosis of HCC. Moreover, we demonstrate that serum HOXA13 may serve as a biomarker for early HCC diagnosing and predicting outcome.
The Tohoku Journal of Experimental Medicine 01/2014; 234(3):209-19. · 1.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Peroxiredoxin 1 (Prdx1) is a member of the peroxiredoxin family of antioxidant enzymes and implicated in cell differentiation, proliferation, and apoptosis. The aim of the present study was to determine the expression and diagnostic and prognostic significance of Prdx1 in human hepatocellular carcinoma (HCC). Prdx1 expression was examined in 76 HCC patients and 20 healthy volunteers. The relationships between Prdx1 expression and clinicopathological features were analyzed. Receiver operating characteristics analysis was used to calculate the diagnostic accuracy of serum Prdx1, serum alpha-fetoprotein (AFP), and their combination. The prognostic impact of Prdx1 on overall survival (OS) and disease-free survival (DFS) of HCC patients was investigated. Prdx1-positive rate was significantly (p < 0.05) higher in HCC (77.1 %) than in adjacent non-tumorous liver tissues (18.4 %). Prdx1 immunoreactivity was positively correlated with tumor vascular endothelial growth factor expression and microvessel density. Prdx1 expression was significantly associated with tumor size, microvascular invasion, Edmondson grade, tumor capsula status, serum AFP, and tumor-node-metastasis stage. The combination of serum Prdx1 and AFP had a markedly higher area under the curve than serum Prdx1 alone. Positive Prdx1 expression was associated with unfavorable OS (p = 0.004) and DFS (p = 0.001). Multivariate analysis revealed intra-tumoral Prdx1 staining as an independent poor prognostic marker for OS (p = 0.006) and DFS (p = 0.002). Taken together, our data suggest that increased Prdx1 expression is associated with tumor angiogenesis and progression in HCC and serves as a promising biomarker for detection and prognosis of this malignancy.
Medical Oncology 01/2014; 31(1):786. · 2.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The association of aberrant expression of Kindlin-2 with tumor progression has been reported in recent years. The purpose of this study was to investigate the expression of Kindlin-2 in hepatocellular carcinoma (HCC), and to evaluate its clinical and prognostic significance. The mRNA and protein levels of Kindlin-2 in HCC and adjacent non-cancerous tissues were examined by real-time PCR and western blotting. The relationships between Kindlin-2 expression, clinicopathological features and postoperative survival of HCC patients were also evaluated. Kindlin-2 expression was higher in HCC tissues as compared to adjacent non-cancerous tissues at both mRNA and protein levels (P < 0.05, respectively). Positive expression of Kindlin-2 was significantly correlated with larger tumor size (P = 0.034), capsular invasion (P = 0.009), microvascular invasion (P = 0.028) and poor prognosis of HCC patients (P < 0.001). Moreover, multivariate survival analysis identified Kindlin-2 as an independent prognostic factor for overall and disease-free survival of HCC patients (P = 0.018 and 0.001, respectively). Taken together, our findings suggested that Kindlin-2 was highly expressed in HCC tissues and was closely related to clinical progression. Therefore, Kindlin-2 protein could be a potential biomarker for predicting poor prognosis of HCC patients after surgery.
Pathology - Research and Practice 01/2014; · 1.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background/Aims: Hepatectomy is associated with high rates of postoperative liver dysfunction in patients with cirrhosis. Since S-adenosyl-L-methionine (SAMe) can be used to treat liver disease, we performed a prospective clinical trial to investigate whether it could be used after hepatectomy to benefit residual liver function. Methodology: We studied 79 hepatitis-related chronic patients who underwent resection of hepatocellular carcinoma; 39 patients were randomly assigned to receive postoperative intravenous SAMe treatment, and 40 were randomly assigned to a control group. The postoperative SAMe treatment consisted of SAMe 1,000mg given intravenously for seven days. The other treatment was standardized. Results: At inclusion into the trial no significant differences were observed between the two groups with respect to gender, age, Child classification, preoperative liver function tests, blood loss, total time of hepatic pedicle occlusion and the extent of liver resection. The overall frequency of postoperative liver insufficiency decreased from 42% in the control group to 31% in the SAMe group, although not statistically significant (p=0.121). When the patients who underwent hepatic pedicle occlusion by Pringle's maneuver over 15min were analyzed, the frequency of postoperative liver insufficiency (p=0.028), serum total bilirubin levels on days 5 (p=0.025) and 7 (p=0.032) preoperatively, and the maximum value of postoperative serum total bilirubin (p=0.040) were significantly greater in the control than in the SAMe group. Conclusions: The results indicate that the postoperative SAMe therapy can benefit residual liver function of the patients with cirrhosis, especially in those suffering greater ischemia reperfusion injury.
[Show abstract][Hide abstract] ABSTRACT: Periostin (PN) is a kind of secreted glycoprotein, which is closely related to the metastatic potential and prognosis of many kinds of tumors in recent studies. However, the expression level of PN in hepatocellular carcinoma (HCC) and its correlation with tumor angiogenesis and prognosis remain unclear. Here Immunohistochemistry assay was used to determine the expression of PN in HCC and corresponding adjacent tissues from 71 patients. VEGF and CD34 were only examined in HCC tissues of patients mentioned above. Immunohistochemically, the expression of PN in HCC was judged to be positive in 73.2 % (52/71) compared with 19.7 % (14/71) in corresponding adjacent tissues, and it was associated with tumor nodules (P = 0.070), microvascular invasion (P = 0.013), Edmondson grade (P = 0.003), tumor capsula (P = 0.038) and TNM stage (P = 0.000); besides, tumors with PN-positive group expressed higher VEGF (82.7 vs. 26.3 %, χ (2) = 20.195, P = 0.000) and had higher MVD (80.5 ± 36.5 vs. 24.0 ± 19.9, t = -6.395, P = 0.000) than those in PN-negative group. Kaplan-Meier method was used for survival analysis, and Cox regression model was performed for multivariate survival analysis. In particular, the expression of PN was found to be an independent factor for predicting overall and disease-free survival of HCC. It is possible that the expression level of PN in HCC is associated with tumor metastatic potential and angiogenesis. Its abnormal expression could be a predictive factor to anticipate HCC patient's prognosis after surgery.
Medical Oncology 03/2013; 30(1):385. · 2.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The docosahexaenoic (DHA), a ω-3 fatty acid, could play a beneficial inhibition of the incidence and progress of a series of human diseases including cancer. It has been report that DHA is involved in cell apoptosis. Recent studies show that the signal transduction pathway links with bcl-2, bax, caspase-3 and MMP-9 molecules. Therefore, we tested the relationship between DHA and cell apoptosis in human hepatocellular carcinoma cells (Bel-7402 cells). We show here that DHA induces Bel-7402 cells apoptosis after pre-treating cells with DHA. DHA down-regulates the protein expression of Bcl-2 and Bim mRNA level, and up-regulates caspase-3 activity and Bax expression level. We also found that DHA inhibits Bel-7402 cells migration. Basic on our studies, DHA may play a role in tumor invasion and survival.
International journal of clinical and experimental pathology 01/2013; 6(2):281-289. · 2.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the results of surgical treatment for primary liver cancer of segment VII or VIII.
The clinical data of 149 patients with primary liver cancer who underwent hepatectomy between January 2005 and December 2010 was retrospectively analyzed. There were 120 male and 29 female patients, aging from 19 to 75 years with a mean of 53.1 years. Among 149 patients, tumors were located at segment VII, VIII or several segments containing VII or VIII (VII/VIII group) in 53 patients, located at other segments (non-VII/VIII group) in 96 patients. The results of surgical treatment for VII/VIII group and non-VII/VIII group were compared by using t test, χ(2) test, Kaplan-Meier survwal analysis and Cox proportion hazard regression analysis.
Right liver lobe was turned over completely in VII/VIII group, hepatic lobe which tumor was located at was not or partly turned over in non-VII/VIII group. Compared with non-VII/VIII group, VII/VIII group had longer operative time ((215 ± 68) min vs. (123 ± 36) min, t = 2.860, P = 0.01). No significant difference was found for tumor size, tumor number, tumor encapsulation, microvascular invasion, Edmondson grade, pTNM stage, intraoperative blood loss, blood transfusion rate, R0 resection rate and postoperative complication rate between two groups. The cumulative 1-, 3-, and 5-year overall survival rates were 74.6%, 42.3%, 15.4% respectively, in VII/VIII group, and 89.3%, 63.0%, 40.4% respectively, in non-VII/VIII group (χ(2) = 13.501, P = 0.000). Univariate and multivariate analysis of prognostic factors indicated that tumor location (tumor was located at segment VII or VIII) had unfavorable prognostic influence on overall survival (χ(2) = 10.329, P = 0.001; HR = 1.693, 95%CI: 1.232 - 2.694, P = 0.013).
The results of surgical treatment for primary liver cancer located at segment VII or VIII are worse than that located at other segments.
Zhonghua wai ke za zhi [Chinese journal of surgery] 06/2012; 50(6):498-501.
[Show abstract][Hide abstract] ABSTRACT: Background/Aims: Radiofrequency ablation (RFA) is a new treatment which is used to treat hepatocellular carcinoma (HCC). We performed this clinical trial to investigate whether it could reduce the damage of residual liver function. Methodology: We studied 40 hepatitis-related chronic patients who underwent RFA for hepatocellular carcinoma. Indocyanine green (ICG) test was performed pre and postoperatively. Results: There were 32 males and 8 females with an average age of 53.98±12.59 years who underwent RFA for HCC. The mean preoperative ICGR15 value of 40 of the patients was (10.17±9.54) lower than the postoperative ICG retention rate at 15 min (ICGR15) value (14.95±12.71). Differences between the preoperative ICGR15 and the postoperative ICGR15 values were not significantly different (p=0.074). The 1-, 2- and 3-year survival rates were 98.7%, 88.8% and 76.4%, respectively. Conclusions: The results indicate that RFA is a minimally invasive treatment which provides a possible treatment modality for HCC patients with poor liver function and the efficacy is as well as the surgical treatment for HCC patients within the Milan criteria.
[Show abstract][Hide abstract] ABSTRACT: Extracellular matrix protein 1 (ECM1) is a glycoprotein involved in a number of biologic processes. To investigate the expression of ECM1 in hepatocellular carcinoma (HCC) and determine its correlation with tumor progression and prognosis, the expression levels of ECM1 in three HCC and one normal liver cell lines, tumor, and corresponding adjacent tissues from 18 HCC patients were analyzed by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. Immunohistochemistry assay was used to determine the expression of ECM1 in HCC and corresponding paracarcinomatous tissues from 77 patients. The results of Western blotting were consistent with the results from RT-PCR analysis of ECM1 mRNA expression. Among the four cell lines, the expression level in HCCLM3, which with the highest metastatic potential, was significantly higher than that with lower (P < 0.05); while ECM1 expression was not detected in normal liver cell line. Expression level of ECM1 was significantly increased in HCC compared with adjacent and normal liver tissues (P < 0.05). Immunohistochemically, the expression of ECM1 in HCC was judged to be positive in 57 (74.0%) cases, significantly higher than that in corresponding paracarcinomatous tissues (P < 0.01), and it was associated with tumor size (P = 0.036), number of tumor nodules (P = 0.048), TNM stage (P = 0.029), and vascular invasion (P = 0.007). In particular, the expression of ECM1 was found to be an independent factor for predicting overall and disease-free survival of HCC. The expression level of ECM1 was associated with metastatic potential of HCC, and its abnormal expression may be used as a predictive factor of unfavorable prognosis and recurrence for HCC after surgery.
Medical Oncology 12/2010; 28 Suppl 1:S318-25. · 2.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate effects of celecoxib (a selective cox-2 inhibitor)combined with fluvastatin (a HMG-CoA reductase inhibitor) on tumor growth and cell apoptosis in hepatocellular carcinoma xenograft in nude mice.
Hepatocellular carcinoma BEL-7402 cells were inoculated subcutaneously into the left armpit of nude mice, the mice (n = 32) were then randomly divided into 4 groups: the control group, the celecoxib group,the fluvastatin group and the combination group. At the end of the study, Tumor Tissues were collected for analysis. Cell apoptosis was determined by flow cytometry analysis and TUNEL assay. Akt, p-Akt and survivin protein levels were measured by Western blot. Statistical comparisons were made using factorial analysis of variance (ANOVA) and multiple comparisons between each two groups were calculated using SNK-q test.
The combination of Celecoxib and fluvastatin resulted in a greater inhibition of tumor growth than either agent alone, the tumor inhibitory rate was 34.0% in the Celecoxib group, 25.0% in the fluvastatin group and 72.2% in the combination group. The percentages of TUNEL--positive cancer cells in the celecoxib and fluvastatin alone treatment groups were 8.5%+/-1.4% and 9.4%+/-1.7% respectively as compared to the control group which was 3.5%+/-0.8%. Combination therapy showed a significantly greater increase in tumor cell apoptosis in comparison with the control and single-therapy groups (apoptotic index: 19.4%+/-3.0%; P value is less than 0.01 versus celecoxib or fluvastatin groups). The results of flow cytometry analysis also showed the same tendency. a small number of apoptotic cells were detected in the control tumours (4.1%+/-1.6%), whereas a large number of apoptotic cells were detected in tumours treated with celecoxib (9.1%+/-2.1%) or fluvastatin (10.1%+/-2.3%) alone; and the combination therapy resulted in even more apoptotic cells (23.6%+/-5.8%; P value is less than 0.01 versus celecoxib or fluvastatin groups). Western blot analysis demonstrated that the combination of celecoxib and fluvastatin significantly down-regulated p-Akt (0.23+/-0.08 versus 1.12+/-0.07 and surviving (0.50+/-0.07 versus 1.47+/-0.19) in BEL-7402 tumours compared with the control (P value is less than 0.01 for all).
The present study provided evidence that treatment with celecoxib in combination with fluvastatin resulted in the inhibition of HCC tumour growth in an in vivo mouse model.
Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology 12/2010; 18(12):900-4.
[Show abstract][Hide abstract] ABSTRACT: To examine the expression of signal transducer and activator of transcription 3 (STAT3) and its activated form (p-STAT3), Twist, and E-cadherin in hepatocellular carcinoma (HCC), and explore their correlations with HCC progression and prognosis.
The expression profiles of STAT3, p-STAT3, Twist, and E-cadherin were assessed on 100 clinical HCC samples and 10 normal liver tissues by using an immunohistochemical staining method, and their correlations with clinicopathologic parameters and survival of HCC patients were statistically analyzed.
The results demonstrated that the positive rate of STAT3, p-STAT3, and Twist in HCC was significantly higher than that in normal liver tissues; furthermore, 52% of HCC lesions showed reduced E-cadherin expression. Correlation analysis indicated that p-STAT3 was positively correlated with Twist expression, whereas Twist was negatively correlated with E-cadherin expression; p-STAT3, Twist, or E-cadherin expression was significantly associated with HCC invasion and metastasis. Survival analysis showed that HCC patients with p-STAT3, Twist positive expression, or reduced E-cadherin expression had a significantly shorter survival duration than those with p-STAT3, Twist negative expression, or those with normal E-cadherin expression. Multivariate analysis identified p-STAT3, Twist, or E-cadherin expression as an independent prognostic factor for overall survival of HCC patients after surgery.
By this study, we suggest that activated STAT3 signal may associate with Twist and E-cadherin expression and mediate HCC invasiveness and metastasis; abnormal p-STAT3/Twist/E-cadherin signal axis may predict poor prognosis of HCC patients.
Journal of Surgical Research 11/2010; 174(1):120-9. · 2.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vasculogenic mimicry (VM), including tubular VM and patterned matrix VM, has been generally recognized as a new pattern of tumor neovascularization. Pilot studies of tubular VM showed that it was present in hepatocellular carcinoma (HCC) and associated with poor clinical prognosis. However, whether patterned matrix VM is clinically significant in HCC is unknown. To elucidate the effects of patterned matrix VM on prognosis of HCC and the mechanisms involved in VM formation, we examined 151 cases of surgically resected human HCC by immunohistochemistry and transmission electron microscopy and conducted hypoxic experiments on human HCC cell line MHCC97-H. We observed 31 of 151 (20.5%) cases exhibited evidence of patterned matrix VM. The expression of patterned matrix VM was associated with larger tumors (P = 0.042), vascular invasion (P = 0.016), high-grade HCC (P = 0.022), and late-stage HCC (P = 0.013). Kaplan-Meier survival analysis revealed that cases of the VM group had lower overall survival (OS) rate (P < 0.001) and disease-free survival (DFS) rate (P = 0.002) than that of the non-VM group. Univariate and multivariate analysis indicated that the presence of patterned matrix VM was independent adverse prognostic factor for both OS (P = 0.004) and DFS (P = 0.011). Expression of hypoxia-inducible factor 1 alpha (HIF-1alpha), matrix metalloproteinase (MMP)-2, and MMP-9 were higher in the VM group than in the non-VM group (P = 0.001, P = 0.030, P = 0.007, respectively). After VM formation was induced by hypoxia, up-regulated expression of HIF-1α, MMP-2, and MMP-9 was also detected in cells cultured under hypoxia condition. Our results indicate that patterned matrix VM exists in HCC, and it might serve as an unfavorable prognostic factor for HCC patients. It is possible that hypoxia via induction of expression of HIF-1alpha, MMP-2, and MMP-9 may enhance VM formation in HCC.
Medical Oncology 10/2010; 28 Suppl 1:S228-38. · 2.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Versican, a large extracellular matrix proteoglycan, accumulates both in tumor stroma and cancer cells. It participates in cell adhesion, migration, and angiogenesis, all features of invasion and metastasis. However, the mechanism(s) whereby versican promotes cancer invasion and metastasis is not yet fully understood. A recent study has documented that versican can activate tumor-infiltrating myeloid cells through toll-like receptor (TLR) 2 and its co-receptors TLR6 and CD14 and elicit the production of proinflammatory cytokines including TNF-alpha that enhance tumor metastasis. As both resident fibroblasts and endothelial cells (ECs) also express functional TLR2 and its co-receptors, we hypothesized that, in addition to myeloid cells, versican may trigger the activation of both fibroblasts and ECs. Of interest, TLR2-mediated activation of EC and fibroblast has been observed to increase the secretion of interleukin-8, a proinflammatory CXC chemokine that potentiates neutrophil infiltration and angiogenesis, as well as metastatic growth. Ligation of TLR2 by versican appears to be directly involved in the activation of multiple types of cells in tumor stroma and the induction of inflammatory cytokine secretion, providing a link between inflammation and cancer metastasis. Accordingly, antagonists of versican and TLR2 restrain the activation of tumor stromal cells, which may offer a novel approach to cancer therapy by targeting tumor microenvironment.
Archives of medical research 06/2009; 40(4):321-3. · 1.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rapamycin (RAPA) inhibits tumor growth and angiogenesis in hepatocellular carcinoma (HCC). The molecular mechanism underlying the antitumoral effects of RAPA remains unclear. Here we established a chemical-induced rat HCC model to investigate the signaling pathways mediating RAPA's antitumor activity. We found that RAPA exposure significantly diminished tumor growth, angiogenesis, and metastasis of HCC. Meanwhile, the antitumor drug dramatically decreased expression of HIF-1alpha and VEGF, either at mRNA or protein levels. Moreover, the low-dose of RAPA (1.5 mg/kg/day) was effective enough to markedly inhibit tumor progression of HCC. The preliminary results suggested that the antitumoral effects of RAPA might be at least partially mediated through downregulation of HIF-1alpha and VEGF, and low-dose RAPA-based regimens exhibited a promising future in treatment of HCC.
Digestive Diseases and Sciences 01/2009; 54(10):2128-36. · 2.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Occurrence of second primary tumors and metastasis remains the major obstacles to prolonged survival of patients with primary hepatocellular carcinoma (HCC). A somatostatin analogue, octreotide, has been previously reported to inhibit the growth of human HCC xenografts in nude mice through its anti-angiogenic activity. It is therefore important to investigate whether octreotide could prevent second primary hepatomas or distant metastasis following resection of primary HCC. In this study, nude mice, bearing the human HCC xenografts with highly metastatic potential (LCI-D20) in the left liver lobe, underwent tumor resection, and received intraperitoneal administration of octreotide or saline as a control for 35 consecutive days. Compared with the control group, octreotide at the doses of 100 and 200 microg/kg/day significantly inhibited the growth (P < 0.001 and P < 0.001, respectively) and incidence of second primary tumors (P = 0.016 and P = 0.001, respectively), decreased lung metastasis (P < 0.001 and P < 0.001, respectively), and prolonged the life span (P = 0.029 and P = 0.006, respectively). Moreover, intratumoral angiogenesis quantified by microvessel density as well as serum and tissue vascular endothelial growth factor (VEGF) levels were considerably decreased in octreotide-treated animals compared to the control animals. These findings suggest that octreotide may prevent the occurrence of second primary hepatomas and lung metastasis after resection of primary HCC, which may be partially attributed to down-regulation of VEGF and subsequent reduction in tumor angiogenesis. Octreotide administration may be useful as an adjuvant therapy to improve survival of patients with HCC.
The Tohoku Journal of Experimental Medicine 01/2009; 218(2):155-60. · 1.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the effect of octreotide on angiogenesis induced by human hepatocellular carcinoma (HCC) and to evaluate whether octreotide can suppress tumor growth in nude mice bearing human HCC xenografts through inhibition of angiogenesis.
Using MTT assay, invasion assay, migration assay, and Matrigel assay, the effects of octreotide on endothelial cells stimulated by vascular endothelial growth factor (VEGF) were evaluated in vitro. MTT assay was also used to investigate the effects of octreotide on human HCC cells with high (MHCC97-H) and low (MHCC97-L) metastatic potential that were established from the animal model of human HCC LCI-D20 in nude mice. The expression of somatostatin receptor (SSTR) subtypes in human umbilical vein endothelial cells (HUVECs), MHCC97-H, and MHCC97-L cells was detected by RT-PCR analysis. An LCI-D20 corneal micropocket model in nude mice was used to evaluate the effect of octreotide on angiogenesis induced by human HCC in vivo. Male nude mice were subcutaneously implanted with LCI-D20 tumor tissues for the tumor xenograft studies. Microvessel density was analyzed in CD34-stained tumor sections by the immunohistochemical SP method.
In vitro, octreotide inhibited the proliferation, invasion, and differentiation of HUVECs elicited by VEGF. RT-PCR analysis demonstrated that HUVECs expressed the somatostatin receptor subtype SSTR3. In vivo, octreotide was sufficiently potent to suppress nude mice corneal neovascularization induced by tumor tissues from LCI-D20. Systemic administrations of octreotide produced a significant suppression of the growth of LCI-D20. In cell culture, MHCC97-H and MHCC97-L cells were insensitive to octreotide at concentrations that significantly inhibited endothelial cells proliferation. The HCC cells used did not express any known SSTRs. Immunohistochemical studies of tumor tissues revealed decreased microvessel density in octreotide-treated animals as compared with controls.
The present study demonstrates that the somatostatin analogue octreotide is a potent antitumor angiogenesis compound and the antiproliferative effect of octreotide on tumor growth in nude mice bearing HCC xenografts may be mediated, at least in part, by its suppressive effect on blood vessel supply. The somatostatin analogue octreotide might provide a useful and relatively nontoxic adjuvant therapy in the treatment of HCC.
Journal of Cancer Research and Clinical Oncology 07/2003; 129(6):327-34. · 2.91 Impact Factor