Showing papers by "Xiao-Dong Zhu published in 2010"

Depletion of Tumor-Associated Macrophages Enhances the Effect of Sorafenib in Metastatic Liver Cancer Models by Antimetastatic and Antiangiogenic Effects

Abstract: Purpose: To investigate the role of macrophages in tumor progression under sorafenib treatment and to explore whether combination of drugs that deplete macrophages improved the antitumor effect of sorafenib. Experimental Design: Tumor growth, lung metastasis, and tumor angiogenesis were observed in HCCLM3-R and SMMC7721, two human hepatocellular carcinoma xenograft nude mouse models, when treated with sorafenib (30 mg/kg daily, n = 6 per group) or a vehicle as control. Macrophage infiltration was measured in the peripheral blood and in sorafenib-treated tumor by immunohistochemistry and flow cytometry with F4/80 antibody and CD11b antibody. The effect of macrophage depletion on tumor angiogenesis and metastasis after sorafenib treatment, using two drug target macrophages, zoledronic acid (ZA) and clodrolip, was measured in the two models of hepatocellular carcinoma. Results: Although sorafenib significantly inhibited tumor growth and lung metastasis, it induced a significant increase in peripheral recruitment and intratumoral infiltration of F4/80- and CD11b-positive cells, which was accompanied with elevation of colony-stimulating factor-1, stromal-derived factor 1α, and vascular endothelial growth factor in the tumor and elevation of plasma colony-stimulating factor-1 and mouse vascular endothelial growth factor in peripheral blood, suggesting the role of macrophages in tumor progression under sorafenib treatment. Depletion of macrophages by clodrolip or ZA in combination with sorafenib significantly inhibited tumor progression, tumor angiogenesis, and lung metastasis compared with mice treated with sorafenib alone. ZA was more effective than clodrolip. Conclusions: Macrophages may have an important role in tumor progression under sorafenib treatment. ZA is promising when combined with sorafenib to enhance its antitumor effect. Clin Cancer Res; 16(13); 3420–30. ©2010 AACR.

Activation of beta-catenin by hypoxia in hepatocellular carcinoma contributes to enhanced metastatic potential and poor prognosis

Abstract: Purpose: Aberrant activation of β-catenin contributes to the malignant phenotype in hepatocellular carcinoma (HCC). Hypoxia is also known to promote HCC invasion and metastasis. However, the association between β-catenin and the proinvasive role of hypoxia remains unclear. We investigated the role of β-catenin in the proinvasive consequences of hypoxia in HCC. Experimental Design: We established in vitro and in vivo hypoxic models to investigate the expression of β-catenin in hypoxic HCC cells and its role in hypoxia-induced aggressiveness. The clinical significance of β-catenin and/or hypoxia-induced factor-1α (HIF-1α) was evaluated using HCC tissue microarrays. Results: Hypoxia induced β-catenin overexpression and/or intracellular accumulation in four HCC cell lines through downregulating the endogenous degradation machinery, and promoted in vitro invasion and in vivo metastasis of MHCC97 and Hep3B cells. Besides morphologic changes, hypoxic MHCC97 and Hep3B cells exhibited molecular alterations consistent with epithelial-mesenchymal transition, characterized by the loss of epithelial cell markers (E-cadherin and plakoglobin) and upregulation of mesenchymal markers (vimentin and N-cadherin), as well as the increase of matrix metalloproteinase 2. However, silencing β-catenin in these hypoxic cells reversed epithelial-mesenchymal transition and repressed metastatic potential. Positive expression of β-catenin in HCC tissue microarray was associated with the expression of HIF-1α ( P = 0.034), and coexpression of β-catenin and HIF-1α in HCC was correlated with shorter overall survival and time to recurrence. Conclusion: β-Catenin in HCC is activated by hypoxia and contributes to hypoxia-induced metastatic potential. Clin Cancer Res; 16(10); 2740–50. ©2010 AACR.

High expression of macrophage colony-stimulating factor-1 receptor in peritumoral liver tissue is associated with poor outcome in hepatocellular carcinoma after curative resection.

Abstract: Background. Macrophage colony-stimulating factor 1 receptor (CSF-1R) expression in hepatocellular carcinoma (HCC) and its prognostic values are unclear. This study evaluated the prognostic values of the intratumoral and peritumoral expression of CSF-1R in HCC patients after curative resection. Methods. Tissue microarrays containing material from cohort 1 (105 patients) and cohort 2 (32 patients) were constructed. Immunohistochemistry was performed and prognostic values of these and other clinicopathological data were evaluated. The CSF-1R mRNA level was assessed by quantitative real-time polymerase chain reaction in cohort 3 (52 patients). Results. Both the CSF-1R density and its mRNA level were significantly higher in peritumoral liver tissue than in the corresponding tumor tissue. CSF-1R was distributed in a gradient in the long-distance peritumoral tissue microarray, with its density decreasing as the distance from the tumor margin increased. High peritumoral CSF-1R was significantly associated with more intrahepatic metastases and poorer survival. Peritumoral CSF-1R was an independent prognostic factor for both overall survival and time to recurrence and affected the incidence of early recurrence. However, intratumoral CSF-1R did not correlate with any clinicopathological feature. Peritumoral CSF-1R was also associated with both overall survival and time to recurrence in a subgroup with small HCCs (< 5c m). Conclusions. Peritumoral CSF-1R is associated with intrahepatic metastasis, tumor recurrence, and patient survivalafterhepatectomy,highlightingthecriticalrole of the peritumoral liver milieu in HCC progression. CSF-1R may become a potential therapeutic target for postoperative adjuvant treatment. The Oncologist 2010; 15:000–000

Residual hepatocellular carcinoma after oxaliplatin treatment has increased metastatic potential in a nude mouse model and is attenuated by Songyou Yin

Abstract: The opposite effects of chemotherapy, which enhance the malignancy of treated cancers such as hepatocellular carcinoma (HCC), are not well understood. We investigated this phenomenon and corresponding mechanisms to develop a novel approach for improving chemotherapy efficacy in HCC. Human hepatocellular carcinoma cell lines HepG2 (with low metastatic potential) and MHCC97L (with moderate metastatic potential) were used for the in vitro study. An orthotopic nude mouse model of human HCC was developed using MHCC97L cells. We then assessed the metastatic potential of surviving tumor cells after in vitro and in vivo oxaliplatin treatment. The molecular changes in surviving tumor cells were evaluated by western blot, immunofluorescence, and immunohistochemistry. The Chinese herbal extract Songyou Yin (composed of five herbs) was investigated in vivo to explore its effect on the metastatic potential of oxaliplatin-treated cancer cells. MHCC97L and HepG2 cells surviving oxaliplatin treatment showed enhanced migration and invasion in vitro. Residual HCC after in vivo oxaliplatin treatment demonstrated significantly increased metastasis to the lung (10/12 vs. 3/12) when re-inoculated into the livers of new recipient nude mice. Molecular changes consistent with epithelial-mesenchymal transition (EMT) were observed in oxaliplatin-treated tumor tissues and verified by in vitro experiments. The Chinese herbal extract Songyou Yin (4.2 and 8.4 g/kg) attenuated EMT and inhibited the enhanced metastatic potential of residual HCC in nude mice (6/15 vs. 13/15 and 3/15 vs. 13/15, respectively). The surviving HCC after oxaliplatin treatment underwent EMT and demonstrated increased metastatic potential. Attenuation of EMT by Songyou Yin may improve the efficacy of chemotherapy in HCC.

Influence of hepatic artery occlusion on tumor growth and metastatic potential in a human orthotopic hepatoma nude mouse model: Relevance of epithelial–mesenchymal transition

Abstract: Hepatic artery ligation (HAL), transarterial embolization (TAE), and transarterial chemoembolization (TACE) have been treatment choices for unresectable hepatocellular carcinoma (HCC). Obstruction of tumor blood supply is one of the most important mechanisms of these therapeutics measures. Here we introduced HAL into a metastatic human HCC orthotopic nude mouse model (using MHCC97L and HepG2 cell lines) to examine the effects of hepatic blood flow obstruction on the metastatic potential of hepatic tumor cells, and to investigate the mechanisms underlying these effects. Our results indicated that HAL inhibited tumor growth but concomitantly elicited tumor adaptation and progression, with increased potential for invasion and distant metastases. The underlying proinvasive mechanism of HAL appeared to be associated with enhanced intratumoral hypoxia and epithelial-mesenchymal transition (EMT) due to hypoxia. This was in accord with the in vitro response of MHCC97L and HepG2 cells to hypoxia. The therapeutic effects of HAL could be enhanced by the phosphatidyl inositol 3-kinase (PI3K) inhibitor LY294002, through arrest of EMT in hepatic tumor cells. It could be useful in the development of mechanism-based combination therapies to enhance the initial antitumor response.

Prognostic value of interleukin 2 and interleukin 15 in peritumoral hepatic tissues for patients with hepatitis B-related hepatocellular carcinoma after curative resection

Abstract: Background and aims Th1/Th2-like cytokine mRNA levels in non-cancerous hepatic tissues from patients with hepatocellular carcinoma (HCC) are associated with metastases and recurrence. This study evaluated the prognostic values of intratumoral and peritumoral Th1/Th2 cytokine protein levels in patients with HCC after curative resection. Methods Two independent cohorts (A and B) of 453 patients with HCC were enrolled. Twelve Th1/Th2 cytokines in tumour and peritumoral hepatic tissues from cohort A (n=192) were quantified with enzyme-linked immunosorbent assays. This cohort was split into training and test sets which were used to identify and verify the prognostic cytokines. The prognostic values of identified cytokines were further validated in cohort B (n=261) using tissue microarray and immunohistochemical staining. Results In the training set, higher interleukin (IL)-2 and IL-15 levels in peritumoral liver tissues, but not in tumour tissues, were significantly associated with a decreased incidence of recurrence of intrahepatic tumour and a prolonged overall survival. This association was verified in the testing set and further validated in patients in cohort B. Importantly, this correlation remained significant in patients with early HCC. Univariate and multivariate analyses indicated that the prognostic performance of peritumoral IL-2 (HR for recurrence=0.4, 95% CI 0.3 to 0.6, p Conclusion Peritumoral IL-2 and IL-15 levels are useful for stratifying patients, even those with early-stage HCC, into subgroups with different prognoses after curative resection.

Gastric carcinoma in China: Current status and future perspectives (Review).

Abstract: Gastric cancer is one of the most frequently occurring cancers in China, with an estimated 380,000 new cases each year, accounting for more than 40% of the worldwide annual cancer incidence. There is geographical clustering of the distribution of gastric cancer in China, with most of the high-risk areas being rural. D2 resection is the standard lymphadenectomy for curative resection in China, but more extensive lymphadenectomy is conducted for selected patients. Perioperative chemotherapy, postoperative chemotherapy or chemoradiotherapy can be combined with surgery. It remains uncertain which option is best, but if surgery is insufficient, adjuvant chemoradiotherapy is recommended. In the palliative setting, although there is no standard first-line chemotherapy, regimens based on taxane, oxaliplatin or capecitabine, or the epirubicin, cisplatin, 5-fluorouracil regimen and its modifications are the most common options selected by Chinese oncologists. Several studies to evaluate target therapy are ongoing, but it is too early to draw any conclusions. However, the development of target therapy is likely to become a milestone in the treatment of gastric cancer.

The p21 Ser31Arg polymorphism and breast cancer risk: a meta-analysis involving 51,236 subjects.

Abstract: Published data on the association between p21 Ser31Arg polymorphism and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Crude ORs with 95% CIs were used to assess the strength of association between the p21 Ser31Arg polymorphism and breast cancer risk. The pooled ORs were performed for co-dominant model (Ser/Arg vs. Ser/Ser, Arg/Arg vs. Ser/Ser), dominant model (Arg/Arg + Ser/Arg vs. Ser/Ser), and recessive model (Arg/Arg vs. Ser/Arg + Ser/Ser). A total of 21 studies including 22,109 cases and 29,127 controls were involved in this meta-analysis. Overall, no significant associations were found between p21 Ser31Arg polymorphism and breast cancer risk when all studies pooled into the meta-analysis. In the subgroup analysis by ethnicity, significantly increased risk was found for Caucasians (Arg/Arg vs. Ser/Ser: OR 1.496, 95% CI 1.164-1.924; and recessive model: OR 1.492, 95% CI 1.161-1.919). When stratified by study design, statistically significantly elevated risk was found for population-based studies (Ser/Arg vs. Ser/Ser: OR 1.085, 95% CI 1.019-1.156). In conclusion, this meta-analysis suggests that the p21 Ser31Arg polymorphism may be associated with breast cancer development in Caucasian. However, large sample and representative population-based studies with homogeneous breast cancer patients and well-matched controls are warranted to confirm this finding.

Long-term interferon-α treatment suppresses tumor growth but promotes metastasis capacity in hepatocellular carcinoma.

Abstract: Purpose To elucidate the effect of IFN-α treatment on tumor growth and metastasis of hepatocellular carcinoma (HCC).

Phase II study of cetuximab in combination with modified FOLFIRI in patients with advanced gastric cancer who failed first-line chemotherapy (EFFI study).

Abstract: 4107 Background: This multicenter, nonrandomized phase II study was launched to evaluate the efficacy and safety of cetuximab in combination with modified FOLFIRI as second-line treatment for advan...