Person: Huang, Peigen
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Huang
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Peigen
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Huang, Peigen
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Publication Solid stress in brain tumours causes neuronal loss and neurological dysfunction and can be reversed by lithium(Springer Science and Business Media LLC, 2019-01-07) Seano, Giorgio; Nia, Hadi; Emblem, Kyrre E.; Datta, Meenal; Ren, Jun; Krishnan, Shanmugarajan; Kloepper, Jonas; Pinho, Marco C.; Ho, William W.; Ghosh, Mitrajit; Askoxylakis, Vasileios; Ferraro, Gino B.; Riedemann, Lars; Gerstner, Elizabeth; Batchelor, Tracy; Wen, Patrick; Lin, Nancy; Grodzinsky, Alan J.; Fukumura, Dai; Huang, Peigen; Baish, James W.; Padera, Timothy; Munn, Lance; Jain, RakeshThe compression of brain tissue by a tumour mass is believed to be a major cause of the clinical symptoms seen in patients with brain cancer. However, the biological consequences of these physical stresses on brain tissue are unknown. Here, via imaging studies in patients and by using mouse models of human brain tumours, we show that a subgroup of primary and metastatic brain tumours, classified as nodular on the basis of their growth pattern, exert solid stress on the surrounding brain tissue, causing a decrease in local vascular perfusion as well as neuronal death and impaired function. We demonstrate a causal link between solid stress and neurological dysfunction by applying and removing cerebral compression, which respectively mimic the mechanics of tumour growth and of surgical resection. We also show that, in mice, treatment with lithium reduces solid-stress-induced neuronal death and improves motor coordination. Our findings indicate that brain-tumour-generated solid stress impairs neurological function in patients, and that lithium as a therapeutic intervention could counter these effects.Publication Overcoming sorafenib evasion in hepatocellular carcinoma using CXCR4-targeted nanoparticles to co-deliver MEK-inhibitors(Nature Publishing Group, 2017) Chen, Yunching; Liu, Ya-Chi; Sung, Yun-Chieh; Ramjiawan, Rakesh R.; Lin, Ts-Ting; Chang, Chih-Chun; Jeng, Kuo-Shyang; Chang, Chiung-Fang; Liu, Chun-Hung; Gao, Dong-Yu; Hsu, Fu-Fei; Duyverman, Annique M.; Kitahara, Shuji; Huang, Peigen; Dima, Simona; Popescu, Irinel; Flaherty, Keith; Zhu, Andrew; Bardeesy, Nabeel; Jain, Rakesh; Benes, Cyril; Duda, DanSorafenib is a RAF inhibitor approved for several cancers, including hepatocellular carcinoma (HCC). Inhibition of RAF kinases can induce a dose-dependent “paradoxical” upregulation of the downstream mitogen-activated protein kinase (MAPK) pathway in cancer cells. It is unknown whether “paradoxical” ERK activation occurs after sorafenib therapy in HCC, and if so, if it impacts the therapeutic efficacy. Here, we demonstrate that RAF inhibition by sorafenib rapidly leads to RAF dimerization and ERK activation in HCCs, which contributes to treatment evasion. The transactivation of RAF dimers and ERK signaling promotes HCC cell survival, prevents apoptosis via downregulation of BIM and achieves immunosuppression by MAPK/NF-kB-dependent activation of PD-L1 gene expression. To overcome treatment evasion and reduce systemic effects, we developed CXCR4-targeted nanoparticles to co-deliver sorafenib with the MEK inhibitor AZD6244 in HCC. Using this approach, we preferentially and efficiently inactivated RAF/ERK, upregulated BIM and down-regulated PD-L1 expression in HCC, and facilitated intra-tumoral infiltration of cytotoxic CD8+ T cells. These effects resulted in a profound delay in tumor growth. Thus, this nano-delivery strategy to selectively target tumors and prevent the paradoxical ERK activation could increase the feasibility of dual RAF/MEK inhibition to overcome sorafenib treatment escape in HCC.Publication Gut Microbiota is critical for the induction of chemotherapy-induced pain(2017) Shen, Shiqian; Lim, Grewo; You, Zerong; Ding, Weihua; Huang, Peigen; Ran, Chongzhao; Doheny, Jason; Caravan, Peter; Tate, Samuel; Hu, Kun; Kim, Hyangin; McCabe, Michael; Huang, Bo; Xie, Zhongcong; Kwon, Douglas; Chen, Lucy; Mao, JianrenChemotherapy-induced pain is a dose-limiting condition that affects 30% of patients undergoing chemotherapy. We found that the gut microbiota promotes the development of chemotherapy-induced mechanical hyperalgesia. Oxaliplatin-induced mechnical hyperalgesia was reduced in germ-free mice and in those mice pretreated with antibiotics. Restoration of the microbiota of germ-free mice abrogated this protection. These effects appear to be mediated, in part, by TLR4 expressed on hematopoietic cells, including macrophages.Publication MicroRNA-378 enhances inhibitory effect of curcumin on glioblastoma(Impact Journals LLC, 2017) Li, Wende; Yang, Weining; Liu, Yujiao; Chen, Siyu; Chin, Shanmin; Qi, Xiaolong; Zhao, Yingchao; Liu, Hao; Wang, Jiasheng; Mei, Xueting; Huang, Peigen; Xu, DonghuiGlioblastoma multiforme is the most aggressive and common primary brain tumor, and is virtually incurable due to its therapeutic resistance to radiation and chemotherapy. Curcumin is a well-known phytochemical exhibiting antitumor activity on many human cancers including glioblastoma multiforme. Given the unique miRNA expression profiles in cancer cells compared to non-cancerous cells, we investigated whether these miRNA could be used to cancer therapy. In this report we show that miR-378, a glioblastoma multiforme down regulated miRNA, may enhance the inhibitory effect of curcumin on this cancer growth. Our results indicated that the inhibitory effect of curcumin was enhanced in miR-378-expressing stable U87 cells in vitro and in vivo, compared to control cells. MiR-378 was found to target p-p38 expression, underlying the observed phenotypic changes. Thus, we concluded that miR-378 enhances the response of glioblastoma multiforme to curcumin treatment, by targeting p38.Publication Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels(Nature Pub. Group, 2013) Chauhan, Vikash; Martin, John D.; Liu, Hao; Lacorre, Delphine A.; Jain, Saloni R.; Kozin, Sergey; Stylianopoulos, Triantafyllos; Mousa, Ahmed S.; Han, Xiaoxing; Adstamongkonkul, Pichet; Popović, Zoran; Huang, Peigen; Bawendi, Moungi G.; Boucher, Yves; Jain, RakeshCancer and stromal cells actively exert physical forces (solid stress) to compress tumour blood vessels, thus reducing vascular perfusion. Tumour interstitial matrix also contributes to solid stress, with hyaluronan implicated as the primary matrix molecule responsible for vessel compression because of its swelling behaviour. Here we show, unexpectedly, that hyaluronan compresses vessels only in collagen-rich tumours, suggesting that collagen and hyaluronan together are critical targets for decompressing tumour vessels. We demonstrate that the angiotensin inhibitor losartan reduces stromal collagen and hyaluronan production, associated with decreased expression of profibrotic signals TGF-β1, CCN2 and ET-1, downstream of angiotensin-II-receptor-1 inhibition. Consequently, losartan reduces solid stress in tumours resulting in increased vascular perfusion. Through this physical mechanism, losartan improves drug and oxygen delivery to tumours, thereby potentiating chemotherapy and reducing hypoxia in breast and pancreatic cancer models. Thus, angiotensin inhibitors —inexpensive drugs with decades of safe use — could be rapidly repurposed as cancer therapeutics.Publication Differential Effects of Sorafenib on Liver Versus Tumor Fibrosis Mediated by Stromal-Derived Factor 1 alpha/C-X-C Receptor Type 4 Axis and Myeloid Differentiation Antigen-Positive Myeloid Cell Infiltration in Mice(Wiley-Blackwell, 2014) Chen, Yunching; Huang, Yuhui; Reiberger, Thomas; Duyverman, Annique M.; Huang, Peigen; Samuel, Rekha; Hiddingh, Lotte; Roberge, Sylvie; Koppel, Christina; Lauwers, Gregory Y.; Zhu, Andrew; Jain, Rakesh; Duda, DanSorafenib—a broad kinase inhibitor—is a standard therapy for advanced hepatocellular carcinoma (HCC) and has been shown to exert antifibrotic effects in liver cirrhosis, a precursor of HCC. However, the effects of sorafenib on tumor desmoplasia—and its consequences on treatment resistance—remain unknown. We demonstrate that sorafenib has differential effects on tumor fibrosis versus liver fibrosis in orthotopic models of HCC in mice. Sorafenib intensifies tumor hypoxia, which increases stromal-derived factor 1 alpha (SDF-1α) expression in cancer and stromal cells and, subsequently, myeloid differentiation antigen–positive (Gr-1+) myeloid cell infiltration. The SDF-1α/C-X-C receptor type 4 (CXCR4) pathway directly promotes hepatic stellate cell (HSC) differentiation and activation through the mitogen-activated protein kinase pathway. This is consistent with the association between SDF-1α expression with fibrotic septa in cirrhotic liver tissues as well as with desmoplastic regions of human HCC samples. We demonstrate that after treatment with sorafenib, SDF-1α increased the survival of HSCs and their alpha-smooth muscle actin and collagen I expression, thus increasing tumor fibrosis. Finally, we show that Gr-1+ myeloid cells mediate HSC differentiation and activation in a paracrine manner. CXCR4 inhibition, using AMD3100 in combination with sorafenib treatment, prevents the increase in tumor fibrosis—despite persistently elevated hypoxia—in part by reducing Gr-1+ myeloid cell infiltration and inhibits HCC growth. Similarly, antibody blockade of Gr-1 reduces tumor fibrosis and inhibits HCC growth when combined with sorafenib treatment. Conclusion: Blocking SDF-1α/CXCR4 or Gr-1+ myeloid cell infiltration may reduce hypoxia-mediated HCC desmoplasia and increase the efficacy of sorafenib treatment. (Hepatology 2014;59:1435-1447)Publication Toll-like Receptor 4 Signaling Confers Cardiac Protection against Ischemic Injury via Inducible Nitric Oxide Synthase- and Soluble Guanylate Cyclase-dependent Mechanisms(Ovid Technologies (Wolters Kluwer Health), 2011) Wang, E; Feng, Yan; Zhang, Ming; Zou, Lin; Li, Yan; Buys, Emmanuel; Huang, Peigen; Brouckaert, Peter; Chao, WeiBackground: Prior administration of a small dose of lipopolysaccharide confers a cardiac protection against ischemia-reperfusion injury. However, the signaling mechanisms that control the protection are incompletely understood. We tested the hypothesis that Toll-like receptor 4 (TLR4) mediates the ability of lipopolysaccharide to protect against cardiac ischemia-reperfusion injury through distinct intracellular pathways involving myeloid differentiation factor 88 (MyD88), TIR-domain-containing adaptor protein-inducing interferon-β-mediated transcription factor (Trif), inducible nitric oxide synthase (iNOS), and soluble guanylate cyclase (sGC). Methods: Wild-type mice and genetically modified mice, that is TLR4-deficient (TLR4−def), TLR2 knockout (TLR2−/−), MyD88−/−, Trif−/−, iNOS−/−, and sGCα1−/−, were treated with normal saline or 0.1 mg/kg lipopolysaccharide intraperitoneally. Twenty-four hours later, isolated hearts were perfused in a Langendorff apparatus and subsequently subjected to 30 min global ischemia and reperfusion for as long as 60 min. Left ventricular function and myocardial infarction sizes were examined. Results: Compared with saline-treated mice, lipopolysaccharide-treated mice had markedly improved left ventricular developed pressure and dP/dtmax (P < 0.01) and reduced myocardial infarction sizes (37.2 ± 3.4% vs. 19.8 ± 4.9%, P < 0.01) after ischemia-reperfusion. The cardiac protective effect of lipopolysaccharide was abolished in the TLR4−def and MyD88−/− mice but remained intact in TLR2−/− or Trif−/− mice. iNOS−/− mice or wild-type mice treated with the iNOS inhibitor 1400W failed to respond to the TLR4-induced nitric oxide production and were not protected by the lipopolysaccharide preconditioning. Although sGCα1−/− mice had robust nitric oxide production in response to lipopolysaccharide, they were not protected by the TLR4-elicited cardiac protection. Conclusions: TLR4 activation confers a potent cardiac protection against ischemia-reperfusion injury via a MyD88-dependent, but Trif-independent, mechanism. iNOS/sGC are essential for the TLR4-induced cardiac protection.Publication Blocking the formation of radiation–induced breast cancer stem cells(Impact Journals LLC, 2014) Wang, YangYang; Li, Wende; Patel, Shalin; Cong, Juan; Zhang, Nan; Sabbatino, Francesco; Liu, Xiaoyan; Qi, Yuan; Huang, Peigen; Lee, Hang; Taghian, Alphonse; Li, Jian-Jian; DeLeo, Albert B.; Ferrone, Soldano; Epperly, Michael W.; Ferrone, Cristina; Ly, Amy; Brachtel, Elena; Wang, XinhuiThe goal of adjuvant (post-surgery) radiation therapy (RT) for breast cancer (BC) is to eliminate residual cancer cells, leading to better local tumor control and thus improving patient survival. However, radioresistance increases the risk of tumor recurrence and negatively affects survival. Recent evidence shows that breast cancer stem cells (BCSCs) are radiation-resistant and that relatively differentiated BC cells can be reprogrammed into induced BCSCs (iBCSCs) via radiation-induced re-expression of the stemness genes. Here we show that in irradiation (IR)-treated mice bearing syngeneic mammary tumors, IR-induced stemness correlated with increased spontaneous lung metastasis (51.7%). However, IR-induced stemness was blocked by targeting the NF-κB- stemness gene pathway with disulfiram (DSF)and Copper (Cu2+). DSF is an inhibitor of aldehyde dehydrogenase (ALDH) and an FDA-approved drug for treating alcoholism. DSF binds to Cu2+ to form DSF-Cu complexes (DSF/Cu), which act as a potent apoptosis inducer and an effective proteasome inhibitor, which, in turn, inhibits NF-κB activation. Treatment of mice with RT and DSF significantly inhibited mammary primary tumor growth (79.4%) and spontaneous lung metastasis (89.6%) compared to vehicle treated mice. This anti-tumor efficacy was associated with decreased stem cell properties (or stemness) in tumors. We expect that these results will spark clinical investigation of RT and DSF as a novel combinatorial treatment for breast cancer.Publication An orthotopic mouse model of hepatocellular carcinoma with underlying liver cirrhosis(Nature Publishing Group, 2015) Reiberger, Thomas; Chen, Yunching; Ramjiwan, Rakesh R.; Hato, Tai; Fan, Christopher; Samuel, Rekha; Roberge, Sylvie; Huang, Peigen; Lauwers, Gregory Y.; Zhu, Andrew; Bardeesy, Nabeel; Jain, Rakesh; Duda, DanSubcutaneous xenografts have been used for decades to study hepatocellular carcinoma (HCC). These models do not reproduce the specific pathophysiological features of HCCs, which occur in cirrhotic livers showing pronounced necroinflammation, abnormal angiogenesis, and extensive fibrosis. As these features are critical for studying the role of the pathologic host microenvironment in tumor initiation, progression, and treatment response, alternative HCC models are desirable. Here, we describe a syngeneic orthotopic HCC model in immunocompetent mice with liver cirrhosis induced by carbon tetrachloride (CCl4) that recapitulates key features of human HCC. Induction of significant hepatic fibrosis requires 12 weeks of CCl4 administration. Intrahepatic implantation of murine HCC cell lines requires 30 minutes per mouse. Tumor growth varies by tumor cell line and mouse strain used. Alternatively, tumors can be induced in a genetically engineered mouse model. In this setting, CCl4 is administered for 12 weeks after tail-vein injection of Cre-expressing adenovirus in Mst1–/–Mst2F/– mice and results in development of HCC tumors (hepatocarcinogenesis) concomitantly to liver cirrhosis.Publication Lifetime Increased Cancer Risk in Mice Following Exposure to Clinical Proton Beam–Generated Neutrons(Elsevier BV, 2014) Gerweck, Leo; Huang, Peigen; Lu, Hsiao-Ming; Paganetti, Harald; Zhou, YenongPurpose To evaluate the lifespan and risk of cancer following whole-body exposure of mice to neutrons generated by a passively scattered clinical SOBP proton beam. Methods and Materials Three hundred young adult female FVB/N mice, 152 test and 148 control, were entered into the experiment. Mice were placed in an annular cassette around a cylindrical phantom, which was positioned lateral to the mid SOBP of a 165 MeV, clinical proton beam. The average distance from the edge of the mid SOBP to the conscious active mice was 21.5 cm. The phantom was irradiated with once daily fractions of 25 Gy, 4 days per week, for 6 weeks. The age at death and cause of death, i.e., cancer and type vs. non-cancer causes, were assessed over the lifespan of the mice. Results Exposure of mice to a dose of 600 Gy of proton beam generated neutrons, reduced the median lifespan of the mice by 4.2% (Kaplan-Meier cumulative survival, P = 0.053). The relative risk of death from cancer in neutron exposed vs. control mice was 1.40 for cancer of all types (P = 0.0006) and 1.22 for solid cancers (P = 0.09). For a typical 60 Gy dose of clinical protons, the observed 22% increased risk of solid cancer would be expected to decrease by a factor of 10. Conclusions Exposure of mice to neutrons generated by a proton dose which exceeds a typical course of radiotherapy by a factor of 10, resulted in a statistically significant increase in the background incidence of leukemia and a marginally significant increase in solid cancer. The results indicate that the risk of out-of-field 2nd solid cancers from SOBP proton generated neutrons and typical treatment schedules, is 6 - 10 times less than is suggested by current neutron risk estimates.