Oncology Research 20(7) Abstracts

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Oncology Research, Vol. 20, pp. 265–274, 2013
0965-0407/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504012X13522227232318
E-ISSN 1555-3906
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Delivery of Paclitaxel and Berbamine by Polymeric Carriers to Cure Gastric Cancer

Lingjun Zhu,*1 Bin Zhang,†1 Xiaowei Lu,‡1 Yongqian Shu,* and Baorui Liu§

*Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China
†Department of Thoracic Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China
‡Department of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China
§The Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing, P.R. China

Successful chemotherapy needs to reduce the toxic side effects against normal tissues and avoid the detriments caused by intolerable solvents. Drug delivery systems using soluble polymeric nanoparticles tend to be the focus. In the current study, core–shell structure nanoparticles were prepared from block copolymer of methoxy poly(ethylene glycol)–polycaprolactone (mPE–PCL). Paclitaxel (PTX) and berbamine (BA) were incorporated into mPEG–PCL nanoparticles. It was found in our study that PTX and BA can be incorporated into the nanoparticles with high encapsulation efficiency. In vitro release study showed that PTX and BA were released from nanoparticles in a sustained manner. In vitro cytotoxicity studies indicated that PTX/BA coloaded nanoparticles (PTX/BA-np) show dose- and time-dependent cytotoxicity again BGC823 cells. Furthermore, intratumoral administration was applied to improve the tumor-targeted delivery in the in vivo evaluation. Compared with free drugs, PTX/BA-np exhibited superior antitumor effect by delaying tumor growth when delivered intratumorally. These results suggest that PTX/BA-np are effective to inhibit the growth of human gastric cancer and merit more research to evaluate the feasibility of clinical application.

Key words: Paclitaxel (PTX); Berbamine (BA); Gastric cancer; Nanoparticle

1These authors provided equal contribution to this study.
Address correspondence to Baorui Liu, The Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing 210008, P.R. China. Tel: +86-25-83105082; Fax: +86-25-83105210; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Yongqian Shu, Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, P.R. China. Tel: +86-25-68136428; Fax:+86-25-68136428; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 275–280, 2013
0965-0407/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504013X13639794277563
E-ISSN 1555-3906
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

In Vitro Repolarized Tumor Macrophages Inhibit Gastric Tumor Growth

Hao Liu,*1 Xiaolin Wu,†1 Shanmei Wang,‡ Wei Deng,§ Lipin Zan,¶ and Shuangjiang Yu#

*Department of Digestion, University-Town Hospital of Chongqing Medical University, Chongqing, China
†Department of Digestion, The Second Affiliated Hospital Chongqing Medical University, Chongqing, China
‡Department of Clinical Laboratory, Henan Provincial People’s Hospital, Henan, China
§Department of Senile Disease, The Second Affiliated Hospital Chongqing Medical University, Chongqing, China
¶Department of Endocrinology, The First Affiliated Hospital Chongqing Medical University, Chongqing, China
#Chongqing Jinmai Biotechnology Company, Chongqing, China

Gastric cancer is the second most frequent cause of cancer-related death worldwide. Combined surgery and chemo/radiotherapy give only a limited 5-year survival rate. Alternative therapeutic strategies such as immunotherapy are needed to improve this survival rate. Macrophages are functionally plastic cells. Type 1 macrophages (M1) inhibit, whereas type 2 macrophages (M2) promote, tumor growth. In this study, we examined the effects of in vitro repolarized tumor macrophages on gastric tumor growth in vivo. We demonstrated that peritoneal macrophages isolated from mouse forestomach carcinoma (MFC) tumor-bearing mice (TPM) displayed a M2 functional phenotype as indicated by a characteristic cytokine production profile and expression pattern of inducible nitric oxide synthase (iNOS) and arginase (Arg) of M2 macrophages. Treatment of TPM with type 1 cytokine IL-12 and IFN-g repolarized TPM toward the M1 phenotype as confirmed by a cytokine production profile and expression pattern of iNOS and Arg of typical M1 macrophages. Repolarized TPM significantly inhibits the growth of MFC tumors implanted subcutaneously compared to peritoneal macrophage (PM) isolated from normal animals, TPM, or M2 macrophages. Our study supports in vitro repolarization of macrophages as a potential immunotherapeutic strategy for gastric cancer.

Key words: Immunotherapy; M1/M2 macrophages; Mouse forestomach carcinoma (MFC); Cytokine; Nitric oxide synthase (iNOS); Arginase

1These authors provided equal contribution to this work.
Address correspondence to Xiaolin Wu, Department of Digestion, The Second Affiliated Hospital, Chongqing Medical University, 400016 Chongqing, China. Tel: 86-023-68485620; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Hao Liu, M.D., Department of Digestion, University-Town Hospital of Chongqing Medical University, Chongqing 400016, China. Tel: 86-023-65714931; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 281–288, 2013
0965-0407/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504013X13639794277608
E-ISSN 1555-3906
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Alterations of Axis Inhibition Protein 1 (AXIN1) in Hepatitis B Virus-Related Hepatocellular Carcinoma and Overexpression of AXIN1 Induces Apoptosis in Hepatocellular Cancer Cells

Jiequn Li,* Hu Quan,† Qiang Liu,† Zhongzhou Si,* Zhijun He,* and Haizhi Qi*

*Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, China
†Department of General Surgery, Hunan Provincial Tumor Hospital, Changsha, China

Axis inhibition protein 1 (AXIN1) is a negative regulator of Wnt/b-catenin signaling via regulating the level of b-catenin. However, the role of AXIN1 in the tumorigenesis and progression of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is less clear. PCR sequence analysis, immunohistochemistry, and Western blot were performed on 22 HBV-related HCC samples and corresponding nontumor liver tissues to detect variants in AXIN1 gene and the expression level of AXIN1. Human hepatoma cell lines SNU475 and SNU423 were transfected with pCDNA3.1-AXIN1-myc or AXIN1 G425S-myc mutant. The growth curve and apoptosis rate of cell lines, phosphorylation of β-catenin, and cell cycle regulatory proteins depending on β-catenin transcriptional activity were detected. We identified four mutations of AXIN1 in 22 primary HBVrelated HCCs and demonstrated a lower expression of AXIN1 in HBV-related HCC tissues than that in paired adjacent nontumor tissues. Overexpression of AXIN1 wild-type but not AXIN1 mutant inhibited the growth of HCC cell lines, accelerated their apoptosis, and negatively regulated β-catenin-dependent transcriptional activity. Our study revealed that alterations of AXIN1 were involved in HBV-related HCC. Overexpression of AXIN1 but not AXIN1 mutant negatively regulated β-catenin-dependent transcriptional activity and downregulated the level of cell cycle regulatory proteins, suggesting that AXIN1 may be a potential target for gene therapy of primary HCC.

Key words: Axis inhibition protein 1 (AXIN1); Gene therapy; Hepatocellular carcinoma (HCC); Mutation

Address correspondence to Haizhi Qi, Department of General Surgery, Second Xiangya Hospital, Central South University, 139 RenMin Road, Changsha, 410011, China. Tel: 086-731-85295808; Fax: 086-731-85295808; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 289–295, 2013
0965-0407/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504013X13639794277644
E-ISSN 1555-3906
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

In Vivo Selection of High-Metastatic Subline of Bladder Cancer Cell and its Characterization

Naoki Sugiyama,* Mihoko Sutoh Yoneyama,*† Shingo Hatakeyama,‡ Hayato Yamamoto,* Akiko Okamoto,* Takuya Koie,* Hisao Saitoh,§ Kanemitsu Yamaya,† Tomihisa Funyu,†§ Takamitsu Inoue,¶ Tomonori Habuchi,¶ Chikara Ohyama,*‡ and Shigeru Tsuboi*†

*Department of Urology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori, Japan
†Department of Biochemistry, Oyokyo Kidney Research Institute, Hirosaki, Aomori, Japan
‡Department of Advanced Transplant and Regenerative Medicine,
Hirosaki University Graduate School of Medicine, Hirosaki, Aomori, Japan
§Department of Urology, Oyokyo Kidney Research Institute, Hirosaki, Aomori, Japan
¶Department of Urology, Akita University Graduate School of Medicine, Akita, Japan

The majority of deaths associated with solid tumors are caused by tumor metastasis. To prevent metastasis, it is vital to understand its detailed process. In hematogenous metastasis of bladder cancer, some cancer cells disseminating into blood circulation extravasate into the lung tissues to form metastases. To study the molecular basis of the lung metastasis of bladder cancer, we employed an in vivo selection system that mimics hematogenous metastasis of bladder cancer on a low-metastatic bladder cancer cell line (KK-47). We have successfully isolated a high-metastatic bladder cancer subline, KK-47HM4, from KK-47 cells. We characterized KK-47HM4 in in vitro experimental systems. No significant difference in growth rate and susceptibility to NK cell attack between KK-47 and KK-47HM4 cells was observed. However, KK-47HM4 exhibited the higher capacities of Matrigel Matrix invasion and transendothelial invasion than KK-47. These results suggest that the extravasation of KK-47HM4 cells was enhanced among the multiple steps of the lung metastasis of bladder cancer. Our cDNA microarray analysis identified 67 genes whose expression was up- or downregulated in KK-47HM4 cells compared with KK-47 cells. This analysis data implied that one possible cause for enhanced extravasation of KK-47HM4 is its higher adhesion to extracellular matrix proteins. KK-47HM4 is the first bladder cancer subline with enhanced extravasation potential using the in vivo selection system. The information provided by our cDNA microarray analysis using KK-47HM4 will be useful for further investigation into the molecular basis of extravasation of cancer cells.

Key words: Bladder cancer; Tumor metastasis; Extravasation; In vivo selection

Address correspondence to Shigeru Tsuboi, Department of Urology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan. Tel: +81-172-39-5091; Fax: +81-172-39-5092; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 297–301, 2013
0965-0407/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504013X13639794277680
E-ISSN 1555-3906
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Ultrasound-Mediated Vascular Endothelial Growth Factor C (VEGF-C) Gene Microbubble Transfection Inhibits Growth of MCF-7 Breast Cancer Cells

Qiuhua Xu,* Ting Sun,† Hua Tian,‡ Changqian Wang,† and Huihong Zhou*

*Department of Ultrasound Imaging, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
†Department of Cardiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
‡State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China

We evaluated the effects of ultrasound-mediated microbubble transfection of VEGF-C siRNA on breast cancer cells in vitro and in vivo. MCF-7 cells were transfected with VEGF-C siRNA and the protein and mRNA expression of VEGF-C was tested using Western blot and qRT-PCR. Twenty nude mice tumors were established by injecting with MCF-7 cells, and were randomized into four groups when palpable tumors reached 190 mm3. The length and width of MCF-7 tumors in mice were measured every 3 days. After 20 days, all mice were killed and the expression of VEGF-C in tumor tissue was also detected by Western blot and qRT-PCR. Results showed that VEGF-C siRNA effectively suppressed the protein and mRNA expression of VEGF-C in MCF-7 cells in vitro. VEGF-C siRNA inhibited the growth of human lymphatic endothelial cells (LECs) and MCF-7 cells. The volume and weight of MCF-7 tumor in VEGF-C siRNA microbubble with irradiation group were reduced with more extent than that in other groups in vivo. The present study highlights that VEGF-C siRNA in combination with ultrasound-mediated microbubble destruction (UMMD) could be a powerful, promising nonviral technology for breast cancer gene therapy.

Key words: Vascular endothelial growth factor C (VEGF-C); Ultrasound-mediated microbubble; Gene therapy

Address correspondence to Ting Sun, Department of Echocardiography, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Hua Tian, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 303–317, 2013
0965-0407/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504013X13639794277761
E-ISSN 1555-3906
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Autocrine-Derived Epidermal Growth Factor Receptor Ligands Contribute to Recruitment of Tumor-Associated Macrophage and Growth of Basal Breast Cancer Cells In Vivo

Nicole K. Nickerson,* Christopher P. Mill,†‡ Hsin-Jung Wu,* David J. Riese II,†§ and John Foley*¶#**

*Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN, USA
†Auburn University Harrison School of Pharmacy, Auburn, AL, USA
‡St. Jude Children’s Research Hospital, Memphis, TN, USA
§Purdue University College of Pharmacy and Purdue University Center for Cancer Research, West Lafayette, IN, USA
¶Indiana University Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
#Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA
**Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA

Epidermal growth factor receptor (EGFR) expression has been linked to progression of basal breast cancers. Many breast cancer cells harbor the EGFR and produce its family of ligands, suggesting they may participate in autocrine and paracrine signaling with cells of the tumor microenvironment. EGFR ligand expression was profiled in the basal breast cancer cell line MDA-231 where AREG, TGF-α, and HBEGF were the three ligands most highly expressed. Autocrine signaling was modulated through silencing or overexpression of these three ligands using lentiviral constructs and the impact measured using motility, proliferation, and cytokine expression assays. Changes in receptor phosphorylation and receptor turnover were examined. Knockdown of AREG or TGF-α in vitro resulted in decreased motility (p < 0.05) and decreased expression of macrophage chemoattractants. Overexpression of TGF-α increased motility and chemoattractant expression, whereas AREG did not. HBEGF modulation had no effect on any cellular behaviors. All the cells with altered ligand production were inoculated into female athymic nude mice to form mammary fat pad tumors, followed by immunohistochemical analysis for necrosis, angiogenesis, and macrophage recruitment. In vivo, knockdown of AREG or TGF-α increased survival (p < 0.001) while decreasing angiogenesis (p < 0.001), tumor growth (p < 0.001), and macrophage attraction (p < 0.001). Overexpression of AREG appeared to elicit a greater effect than TGF-α on mammary fat pad tumor growth by increasing angiogenesis (p < 0.001) and macrophage attraction to the tumor (p < 0.01). We propose these changes in mammary tumor growth were the result of increased recruitment of macrophages to the tumor by cells with altered autocrine EGFR signaling. We conclude that AREG and TGF-α were somewhat interchangeable in their effects on EGFR signaling; however, TGF-α had a greater effect in vitro and AREG had a greater effect in vivo.

Key words: Epidermal growth factor receptor (EGFR); Amphiregulin; Breast cancer; Transforming growth factor-α (TGF-α); Macrophage colony-stimulating factor-1 (MCSF-1)

Address correspondence to John Foley, Medical Sciences, Indiana University, Jordan Hall 104, Bloomington, IN 47405, USA. Tel: 812-855-3189; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 319–326, 2013
0965-0407/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504013X13644751511888
E-ISSN 1555-3906
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

FIM-A, a Phosphorus-Containing Sirolimus, Inhibits the Angiogenesis and Proliferation of Osteosarcomas

Wei-Nan Liu,* Jian-Hua Lin,* Yuan-Rong Cheng,† Li Zhang,‡ Jie Huang,† Zhao-Yang Wu,* Fa-Sheng Wang,* Sheng-Gui Xu,*§ Wen-Ping Lin,*¶ Wen-Bin Lan,* and Guo-Xin Yang†

*The First Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
†Fujian Institute of Microbiology, Fuzhou, Fujian, China
‡School of Traumatology and Orthopedics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
§Department of Orthopedics, Mindong Hospital of Ningde, Fujian, China
¶Department of Orthopedics, The 2nd Affiliated Hospital of Fujian Medical University, Fujian, China

The mTOR pathway is a central control of cell growth, proliferation, metabolism, and survival, and is deregulated in most cancers. Cancer cells are addicted to increased activity of mTOR kinase-mediated signaling pathways, leading to numerous inhibitors of mTOR signaling in preclinic and clinical trials for cancer therapy. Phosphorus-containing sirolimus (FIM-A), which targets mTOR signaling, inhibits cancer cell growth in vitro. Here we report that FIM-A reduces the angiogenesis and proliferation of osteosarcoma both in vitro and in vivo. In cultured osteosarcoma cell lines, FIM-A inhibited cell proliferation and arrested cells in the G1 phase of the cell cycle, accompanied with reduction of VEGF and HIF-1α. With in vivo mouse osteosarcoma xenografts, FIM-A treatment resulted in the inhibition of mTORC1 signaling as demonstrated by the decreased phosphorylation of p70S6K1 and 4E-BP1. Consistent with this finding, FIM-A significantly decreased the average tumor volume, nuclei staining of PCNA, and the number of intratumoral microvessels. Our data demonstrated that targeting mTORC1 by FIM-A inhibited the growth of osteosarcoma in vitro and in vivo, providing the basis for further development of FIM-A as a therapy for osteosarcoma patients.

Key words: FIM-A; Osteosarcoma; mTOR; Antiproliferation; Antiangiogenesis

Address correspondence to Jian-Hua Lin, Department of Orthopedics, The First Affiliated Hospital of Fujian Medical University, No. 20, Chazhong, Road, 350005, Fujian Province, China. Tel: 008659187982001; Fax: 008659187982001; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Oncology Research, Vol. 20, pp. 327–332, 2013
0965-0407/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096504013X13639794277725
E-ISSN 1555-3906
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

A Phase II Study of Preoperative Chemotherapy With Modified FOLFOX6 Followed by Surgery and Postoperative Chemoradiation in Patients With Localized Gastric Adenocarcinoma

Shao-shui Chen,*1 Xiao-chun Yang,†1 Feng Chi,‡1 Wen-zheng Yu,§ Zhen-bo Wang,* Fang-ling Ning,* Ze-shun Yu,* Yan-zhang Hao,* Mian-li Li,* Feng Wang,* Dian-zhong Geng,* Li-hua Liu,* Xin-Jun Dong,* Xian-zhong Peng,* and Chun-xiang Ji*

*Department of Oncology, Affiliated Hospital of Binzhou Medical University, Binzhou, China
†Department of Emergency, People’s Hospital of Binzhou, Binzhou, China
‡Department of Radiotherapy, Cancer Center, Sun Yat-Sen University, Guangzhou, China
§Department of Hematology, Affiliated Hospital of Binzhou Medical University, Binzhou, China

The optimal neoadjuvant and adjuvant treatment for gastric cancer remains controversial. We conducted a phase II study using preoperative chemotherapy with modified FOLFOX6 followed by surgical resection and postoperative chemoradiation in patients with gastric carcinoma. Preoperative chemotherapy (two or three cycles) consisted of a 2-h infusion of oxaliplatin (100 mg/m2) and folinic acid (100 mg/m2) followed by a 46-h continuous infusion of 5-fluorouracil (5-FU; 2,400 mg/m2). Surgical resection was planned 4 weeks after the last chemotherapy cycle. Patients underwent postsurgical chemoradiation, receiving a total dose of 45 Gy and 5-FU continuous infusion (350 mg/m2/day). The primary end points were feasibility, overall response rate, and R0 resectability rate after preoperative chemotherapy. The secondary end points were tolerability, treatment-associated complications, disease-free survival, and overall survival. Nineteen patients were enrolled in this study. After neoadjuvant treatment, four patients (21.1%) experienced progressive disease, six patients (31.6%) showed partial remission, and nine patients (47.3%) showed stable disease. In 15 patients (78.9%) R0 resectability could be achieved. Eleven of these patients (73.3%) were able to undergo postoperative chemoradiation. Notably, eight (72.7%) of these patients were disease free and alive at median follow-up of 60 months. Chemotherapy associated neutropenia, neutropenic fever, and anastomotic dehiscence were observed. The combination of preoperative chemotherapy and postoperative chemoradiation is feasible in a significant subset of gastric cancer patients.

Key words: Gastric cancer; FOLFOX6; Chemotherapy; Chemoradiotherapy

1These authors provided equal contribution to this work.
Address correspondence to Shao-shui Chen, Department of Oncology, Affiliated Hospital of Binzhou Medical University, No. 661, Yellow-River Second Street, 256603, Binzhou, China. Tel: +86-0543-3258689; Fax: +86-0543-3258689; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it