You are here

Zhang, Xuefeng

Positions:

Assistant Professor of Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1995

M.D. — China Medical University (China)

Residency, Pathology

Peking Union Medical College (China)

Doctoral Student, Pathology

Peking Union Medical College (China)

Research Fellow, Pathology

Harvard University

Residency, Pathology

University of Chicago

Fellowship, Pathology

University of Chicago

Publications:

A Rapidly Enlarging Müllerian-Derived Hepatic Adenomyoma Clinically Mimicking Hepatic Adenoma in a Pregnant Woman.

Authors
Luedke, C; Ravindra, K; Hertzberg, B; Berg, C; Bentley, R; Zhang, X
MLA Citation
Luedke, C, Ravindra, K, Hertzberg, B, Berg, C, Bentley, R, and Zhang, X. "A Rapidly Enlarging Müllerian-Derived Hepatic Adenomyoma Clinically Mimicking Hepatic Adenoma in a Pregnant Woman." The American journal of gastroenterology 112.8 (August 2017): 1217-.
PMID
28766580
Source
epmc
Published In
The American Journal of Gastroenterology (Elsevier)
Volume
112
Issue
8
Publish Date
2017
Start Page
1217
DOI
10.1038/ajg.2017.158

Radiographic and endoscopic regression of metastatic gastric cancer to the colon in the setting of 5-aminosalicylic acid use.

Colonic metastases from gastric cancer are a rare phenomenon and sparsely reported in the literature. We report a case of a 59-year-old woman who presented with vague abdominal symptoms and initial computer tomography (CT) imaging suggestive of a colonic apple-core lesion with serial colonoscopic biopsies diagnostic of metastatic signet ring cell gastric adenocarcinoma. This case is unique given the evolving CT and endoscopic findings that suggested a regression in colonic wall thickening in the setting of 5-aminosalicylic acid (5-ASA) use prior to histologic diagnosis.

Authors
Patel, YA; McCall, SJ; Zhang, X; Jaffe, T; Shimpi, RA
MLA Citation
Patel, YA, McCall, SJ, Zhang, X, Jaffe, T, and Shimpi, RA. "Radiographic and endoscopic regression of metastatic gastric cancer to the colon in the setting of 5-aminosalicylic acid use." Journal of gastrointestinal oncology 7.6 (December 2016): E88-E92.
PMID
28078130
Source
epmc
Published In
Journal of Gastrointestinal Oncology
Volume
7
Issue
6
Publish Date
2016
Start Page
E88
End Page
E92
DOI
10.21037/jgo.2016.05.02

Mixed Adenoneuroendocrine Carcinoma, Amphicrine Type, of the Small Bowel.

Amphicrine-type mixed adenoneuroendocrine carcinomas are exceedingly rare lesions of the gastrointestinal tract, comprising tumor cells simultaneously demonstrating both neuroendocrine and exocrine features. To date, only 14 cases of amphicrine carcinoma have been reported; here we report the first definitive case of amphicrine carcinoma in the small bowel.A 72-year-old woman who sought treatment for nonspecific abdominal complaints was found to have a duodenojejunal junction tumor and underwent radical surgical resection.Morphologically, the tumor consisted of areas of moderately differentiated adenocarcinoma intermingled with areas characteristic of neuroendocrine tumor. The entire tumor showed strong, diffuse immunoreactivity for synaptophysin. Coexpression of exocrine and neuroendocrine features by neoplastic cells indicates bivalent differentiation, and therefore the tumor was classified as an amphicrine carcinoma of the small bowel.Demonstration of amphicrine carcinoma in the small bowel carries implications with regard to the common origin of exocrine and neuroendocrine cells in the gastrointestinal tract.

Authors
Ludmir, EB; McCall, SJ; Cardona, DM; Perkinson, KR; Guy, CD; Zhang, X
MLA Citation
Ludmir, EB, McCall, SJ, Cardona, DM, Perkinson, KR, Guy, CD, and Zhang, X. "Mixed Adenoneuroendocrine Carcinoma, Amphicrine Type, of the Small Bowel." American journal of clinical pathology 145.5 (May 2016): 703-709.
PMID
27124941
Source
epmc
Published In
American Journal of Clinical Pathology
Volume
145
Issue
5
Publish Date
2016
Start Page
703
End Page
709
DOI
10.1093/ajcp/aqw028

Early and Severe Radiation Esophagitis Associated With Concurrent Sirolimus

Authors
Akthar, AS; Golden, DW; Nanda, R; Sharma, MR; Te, HS; Reddy, KG; Zhang, X; Malik, R
MLA Citation
Akthar, AS, Golden, DW, Nanda, R, Sharma, MR, Te, HS, Reddy, KG, Zhang, X, and Malik, R. "Early and Severe Radiation Esophagitis Associated With Concurrent Sirolimus." Journal of Clinical Oncology 34.9 (March 20, 2016): e73-e75.
Source
crossref
Published In
Journal of Clinical Oncology
Volume
34
Issue
9
Publish Date
2016
Start Page
e73
End Page
e75
DOI
10.1200/JCO.2013.50.1643

Expression of SOX9 and CDX2 in nongoblet columnar-lined esophagus predicts the detection of Barrett's esophagus during follow-up.

The diagnosis of Barrett's esophagus in the United States requires both endoscopically evident columnar-lined esophagus and the presence of goblet cells by histology. Currently, there is no consensus on how patients with nongoblet columnar-lined esophagus should be followed. In this study, we investigated whether biomarkers can be used to predict the detection of goblet cells in follow-up biopsies. Patients with nongoblet columnar-lined esophagus were identified. In 13 of these cases, goblet cells were detected in subsequent follow-up endoscopic biopsies (Barrett's group). Additionally, 26 cases that remained negative for goblet cells in follow-up biopsies served as controls. Immunohistochemistry for CDX2, SOX9, BMP4, SHH, and MUC2 was performed on the initial biopsies and graded independently by at least two pathologists in a masked manner. CDX2 was positive in the nongoblet columnar epithelium of 7/13 cases in the Barrett's group and in 4/26 controls (sensitivity 54%, specificity of 85%, odds ratio (OR) 6.4). Strong and diffuse immunoreactivity for SOX9 was detected in 10/13 cases in the Barrett's group and in 1/26 controls (sensitivity 77%, specificity 96%, OR 83.3). Combining CDX2 and SOX9 as a panel increased sensitivity to 85%, although the specificity decreased to 85% (OR 30.3). SHH, BMP4, and MUC2 expression showed no significant difference between the Barrett's and control groups. In patients with nongoblet columnar-lined esophagus, SOX9 and CDX2 may be useful in identifying a subset of patients who have a higher risk of being diagnosed for Barrett's esophagus (developing goblet cells) and need closer follow-up.

Authors
Zhang, X; Westerhoff, M; Hart, J
MLA Citation
Zhang, X, Westerhoff, M, and Hart, J. "Expression of SOX9 and CDX2 in nongoblet columnar-lined esophagus predicts the detection of Barrett's esophagus during follow-up." Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 28.5 (May 2015): 654-661.
PMID
25412842
Source
epmc
Published In
Modern Pathology
Volume
28
Issue
5
Publish Date
2015
Start Page
654
End Page
661
DOI
10.1038/modpathol.2014.157

Pancreatic ductal adenocarcinoma with autoimmune pancreatitis-like histologic and immunohistochemical features.

Autoimmune pancreatitis (AIP) often manifests as a mass lesion causing obstructive jaundice, clinically mimicking pancreatic carcinoma. A diagnosis of AIP may obviate the need for surgical resection, as most patients respond to steroid treatment. However, it is not clear whether these 2 conditions can coexist. In this study, 105 specimens resected for pancreatic ductal adenocarcinoma (PDAC) that also have changes of chronic pancreatitis were examined for features considered to be characteristic of AIP. Of 105 cases of PDAC with changes of chronic pancreatitis, 10 (9.5%) exhibited histologic features of AIP, including exuberant fibrosis, lymphoplasmacytic infiltration, obliterative phlebitis, or granulocytic epithelial lesions. Of these 10 cases, 7 had more than 20 immunoglobulin G4+ plasma cells per high-power field. Of these 7 cases, 5 were analyzed for Kirsten rat sarcoma viral oncogene mutation and SMAD4 expression. Three cases showed K-ras mutation and/or loss of SMAD4 expression in benign AIP-like areas. These findings suggest 2 possibilities: first, AIP-like lesions may occur in a small but significant portion of PDAC cases; second, some PDACs may arise in a background of AIP. Therefore, caution is necessary when making a diagnosis of AIP by needle biopsy of a mass lesion, and patients with a tentative AIP diagnosis should be closely followed up clinically.

Authors
Zhang, X; Liu, X; Joseph, L; Zhao, L; Hart, J; Xiao, S-Y
MLA Citation
Zhang, X, Liu, X, Joseph, L, Zhao, L, Hart, J, and Xiao, S-Y. "Pancreatic ductal adenocarcinoma with autoimmune pancreatitis-like histologic and immunohistochemical features." Human pathology 45.3 (March 2014): 621-627.
PMID
24457081
Source
epmc
Published In
Human Pathology
Volume
45
Issue
3
Publish Date
2014
Start Page
621
End Page
627
DOI
10.1016/j.humpath.2013.08.027

Incidence and prognostic impact of high-risk HPV tumor infection in cervical esophageal carcinoma

© Pioneer Bioscience Publishing Company. All rights reserved. Background: Cervical esophageal carcinoma (CEC) is an uncommon malignancy. Limited data supports the use of definitive chemoradiotherapy (CRT) as primary treatment. Furthermore, the role of human papillomavirus (HPV) tumor infection in CEC remains unknown. This study retrospectively analyzes both outcomes of CEC patients treated with CRT and the incidence and potential role of HPV tumor infection in CEC lesions. Methods: A total of 37 CEC patients were treated with definitive CRT at our institution between 1987 and 2013. Of these, 19 had tumor samples available for high-risk HPV (types 16 and 18) pathological analysis. Results: For all patients (n=37), 5-year overall survival (OS), disease-free survival (DFS), and loco-regional control (LRC) rates were 34.1%, 40.2%, and 65.6%, respectively. On pathological analysis, 1/19 (5.3%) patients had an HPV-positive lesion. Conclusions: Definitive CRT provides disease-related outcomes comparable to surgery. Moreover, HPV tumor infection in CEC is uncommon and its prognostic role is unclear. Our data contribute to the construction of an anatomical map of HPV tumor infection in squamous cell carcinomas (SCC) of the upper aerodigestive tract, and suggest a steep drop in viral infection rates at sites distal to the oropharynx, including the cervical esophagus.

Authors
Ludmir, EB; Palta, M; Zhang, X; Wu, Y; Willett, CG; Czito, BG
MLA Citation
Ludmir, EB, Palta, M, Zhang, X, Wu, Y, Willett, CG, and Czito, BG. "Incidence and prognostic impact of high-risk HPV tumor infection in cervical esophageal carcinoma." Journal of Gastrointestinal Oncology 5.6 (January 1, 2014): 401-407.
Source
scopus
Published In
Journal of Gastrointestinal Oncology
Volume
5
Issue
6
Publish Date
2014
Start Page
401
End Page
407
DOI
10.3978/j.issn.2078-6891.2014.05

A subset of rosai-dorfman disease exhibits features of IgG4-related disease

In this study we investigated the distribution of IgG4+ plasma cells and regulatory T (TREG) cells, a major regulator of IgG4 production, in nodal and extranodal Rosai-Dorfman disease (RDD). Twenty-six specimens (15 nodal, 11 extranodal) were examined, with reactive lymph nodes and site-matched extranodal specimens as controls. Overall, 84.6% (22/26) of the specimens showed various degrees of sclerosis (7 mild, 8 moderate, and 7 severe). Nineteen cases (73.1%) exhibited more than 10 IgG4+ cells/0.060 mm2 (photographed area at ×40), and 8 cases (30.8%) showed more than 40% of IgG+ cells being IgG4+. Only 1 control case exhibited more than 10 IgG4+ cells/0.060 mm2 (P < .05). The number of TREG cells was comparable between nodal RDD and controls, whereas extranodal RDD exhibited significantly higher numbers of TREG cells than controls. These findings demonstrate that a subset of RDD shows features of IgG4-related disease and indicate an overlap between certain aspects of the 2 diseases. © American Society for Clinical Pathology.

Authors
Zhang, X; Hyjek, E; Vardiman, J
MLA Citation
Zhang, X, Hyjek, E, and Vardiman, J. "A subset of rosai-dorfman disease exhibits features of IgG4-related disease." American Journal of Clinical Pathology 139.5 (2013): 622-632.
PMID
23596114
Source
scival
Published In
American Journal of Clinical Pathology
Volume
139
Issue
5
Publish Date
2013
Start Page
622
End Page
632
DOI
10.1309/AJCPARC3YQ0KLIOA

Immunohistochemistry for immunoglobulin G4 on paraffin sections for the diagnosis of pemphigus

Context.-Pemphigus is a group of autoimmune vesiculobullous diseases characterized by immunoglobulin G (IgG) antibodies directed against desmosomal adhesion proteins, with IgG4 being the predominant subclass in active diseases. Direct immunofluorescence for IgG performed on fresh-frozen tissue plays a crucial role in diagnosing pemphigus. However, the diagnosis might be hindered when frozen tissue is not available. Objective.-To evaluate the usefulness of immunohistochemistry for IgG4 performed on paraffin sections as a diagnostic test for pemphigus. Design.-Eighteen immunofluorescence-proven pemphigus cases (12 pemphigus vulgaris, 6 pemphigus foliaceus) were studied. Four normal skin specimens and 32 nonpemphigus vesiculobullous disease specimens served as controls. Paraffin sections of all cases were examined immunohistochemically for IgG4 expression. Positivity was defined as distinct, condensed, continuous immunoreactivity localized to the intercellular junctions of keratinocytes. Results.-The immunostains were independently evaluated in a masked manner by 3 pathologists, with a 100% interobserver agreement. Nine of 12 pemphigus vulgaris cases (sensitivity 75.0%), and 4 of 6 pemphigus foliaceus cases (sensitivity 66.7%), were positive for IgG4 immunostain. The overall sensitivity was 72.2%. One control specimen (bullous pemphigoid) showed IgG4 positivity (specificity 97.2%). In specimens demonstrating acantholysis, 8 of 10 pemphigus vulgaris cases (sensitivity 80.0%) and 4 of 4 pemphigus foliaceus cases (sensitivity 100.0%) were positive for IgG4. The overall sensitivity for specimens with acantholytic lesions was 85.7%. Conclusion.-Immunohistochemistry for IgG4 provides a reasonably sensitive and highly specific test for diagnosing pemphigus, especially when frozen tissue is not available, and active acantholytic lesions are examined.

Authors
Zhang, X; Hyjek, E; Soltani, K; Petronic-Rosic, V; Shea, CR
MLA Citation
Zhang, X, Hyjek, E, Soltani, K, Petronic-Rosic, V, and Shea, CR. "Immunohistochemistry for immunoglobulin G4 on paraffin sections for the diagnosis of pemphigus." Archives of Pathology and Laboratory Medicine 136.11 (2012): 1402-1407.
PMID
23106586
Source
scival
Published In
Archives of Pathology and Laboratory Medicine
Volume
136
Issue
11
Publish Date
2012
Start Page
1402
End Page
1407
DOI
10.5858/arpa.2011-0425-OA

Bilateral breast involvement by disseminated extranodal Rosai-Dorfman disease.

Authors
Gwin, K; Cipriani, N; Zhang, X; Schmidt, R; Hyjek, E
MLA Citation
Gwin, K, Cipriani, N, Zhang, X, Schmidt, R, and Hyjek, E. "Bilateral breast involvement by disseminated extranodal Rosai-Dorfman disease." The breast journal 17.3 (May 2011): 309-311.
PMID
21450017
Source
epmc
Published In
The Breast Journal
Volume
17
Issue
3
Publish Date
2011
Start Page
309
End Page
311
DOI
10.1111/j.1524-4741.2011.01072.x

Thrombospondin-1 modulates vascular endothelial growth factor activity at the receptor level.

Vascular endothelial growth factor (VEGF) is a well-established stimulator of vascular permeability and angiogenesis, whereas thrombospondin-1 (TSP-1) is a potent angiogenic inhibitor. In this study, we have found that the TSP-1 receptors CD36 and beta1 integrin associate with the VEGF receptor 2 (VEGFR2). The coclustering of receptors that regulate angiogenesis may provide the endothelial cell with a platform for integration of positive and negative signals in the plane of the membrane. Thus, this complex may represent a molecular switch that regulates angiogenesis and determines endothelial cell behavior. In this context, physiological levels of TSP-1 appear to support VEGFR2 function on both the cellular and tissue level, because phosphorylation of VEGFR2 and vascular permeability in response to VEGF are decreased in TSP-1-null mice and isolated endothelial cells. A therapeutic agent based on the antiangiogenic domain of TSP-1, designated 3TSR (for three TSP-1 type 1 repeats), has significant antiangiogenic and antitumor efficacy. Systemic treatment of wild-type mice with 3TSR significantly decreased VEGF-induced permeability. Consistent with this result, VEGF-stimulated phosphorylation of VEGFR2 was also significantly decreased in lung extracts from 3TSR-treated mice. Moreover, 3TSR significantly decreased VEGF-stimulated VEGFR2 phosphorylation in human dermal microvascular endothelial cells in culture. Taken together, the results indicate that TSP-1 and 3TSR modulate the function of VEGFR2.

Authors
Zhang, X; Kazerounian, S; Duquette, M; Perruzzi, C; Nagy, JA; Dvorak, HF; Parangi, S; Lawler, J
MLA Citation
Zhang, X, Kazerounian, S, Duquette, M, Perruzzi, C, Nagy, JA, Dvorak, HF, Parangi, S, and Lawler, J. "Thrombospondin-1 modulates vascular endothelial growth factor activity at the receptor level." FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23.10 (October 2009): 3368-3376.
PMID
19528255
Source
epmc
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
23
Issue
10
Publish Date
2009
Start Page
3368
End Page
3376
DOI
10.1096/fj.09-131649

A double hit to kill tumor and endothelial cells by TRAIL and antiangiogenic 3TSR.

As tumor development relies on a coordination of angiogenesis and tumor growth, an efficient antitumor strategy should target both the tumor and its associated vessels. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a tumor-selective manner. Additionally, thrombospondin-1, a naturally occurring inhibitor of angiogenesis, and a recombinant protein containing functional domains of thrombospondin-1, 3TSR, have been shown to be necessary and sufficient to inhibit tumor angiogenesis. Here, we show that a combination of a TRAIL receptor 2 agonist antibody, Lexatumumab, and 3TSR results in a significantly enhanced and durable tumor inhibition. We further observed that 3TSR induces apoptosis in primary endothelial cells by up-regulating the expression of TRAIL receptors 1 and 2 in a CD36 and Jun NH(2)-terminal kinase-dependent manner leading to the activation of both intrinsic and extrinsic apoptotic machineries. The modulation of these pathways is critical for 3TSR-induced apoptosis as disrupting either via specific inhibitors reduced apoptosis. Moreover, 3TSR attenuates the Akt survival pathway. These studies indicate that 3TSR plays a critical role in regulating the proapoptotic signaling pathways that control growth and death in endothelial cells and that a combination of TRAIL and 3TSR acts as a double hit against tumor and tumor-associated vessels.

Authors
Ren, B; Song, K; Parangi, S; Jin, T; Ye, M; Humphreys, R; Duquette, M; Zhang, X; Benhaga, N; Lawler, J; Khosravi-Far, R
MLA Citation
Ren, B, Song, K, Parangi, S, Jin, T, Ye, M, Humphreys, R, Duquette, M, Zhang, X, Benhaga, N, Lawler, J, and Khosravi-Far, R. "A double hit to kill tumor and endothelial cells by TRAIL and antiangiogenic 3TSR." Cancer research 69.9 (May 2009): 3856-3865.
PMID
19366809
Source
epmc
Published In
Cancer Research
Volume
69
Issue
9
Publish Date
2009
Start Page
3856
End Page
3865
DOI
10.1158/0008-5472.can-08-2940

Thrombospondin-based antiangiogenic therapy.

Thrombospondins (TSPs) are a family of extracellular matrix proteins that regulate tissue genesis and remodeling. TSP-1 plays a pivotal role in the regulation of both physiological and pathological angiogenesis. The inhibitory effects of TSP-1 on angiogenesis have been established in numerous experimental models. Among other TSP members, TSP-2 has equivalent domain structure as TSP-1 and shares most functions of TSP-1. The mechanisms by which TSP-1 and -2 inhibit angiogenesis can be broadly characterized as direct effects on vascular endothelial cells and indirect effects on the various angiogenic regulators. The fact that TSP-1 and -2 are potent endogenous angiogenic inhibitors has prompted studies to explore their therapeutic applications, and detailed understanding of the mechanisms of action of TSP-1 and -2 has facilitated the design of therapeutic strategies to optimize these activities. The therapeutic effects can be achieved by up-regulation of endogenous TSPs, or by the delivery of recombinant proteins or synthetic peptides that contain sequences from the angiogenic domain of TSP-1. In this article, we review the progress in thrombospondin-based antiangiogenic therapy and discuss the perspectives on the significant challenges that remain.

Authors
Zhang, X; Lawler, J
MLA Citation
Zhang, X, and Lawler, J. "Thrombospondin-based antiangiogenic therapy." Microvascular research 74.2-3 (September 2007): 90-99. (Review)
PMID
17559888
Source
epmc
Published In
Microvascular Research
Volume
74
Issue
2-3
Publish Date
2007
Start Page
90
End Page
99
DOI
10.1016/j.mvr.2007.04.007

Adeno-associated virus-mediated antiangiogenic gene therapy with thrombospondin-1 type 1 repeats and endostatin.

PURPOSE: Recombinant adeno-associated virus (rAAV)-mediated antiangiogenic gene therapy offers a powerful strategy for cancer treatment, maintaining sustained levels of antiangiogenic factors with coincident enhanced therapeutic efficacy. We aimed to develop rAAV-mediated antiangiogenic gene therapy delivering endostatin and 3TSR, the antiangiogenic domain of thrombospondin-1. EXPERIMENTAL DESIGN: rAAV vectors were constructed to express endostatin (rAAV-endostatin) or 3TSR (rAAV-3TSR). The antiangiogenic efficacy of the vectors was characterized using a vascular endothelial growth factor (VEGF)-induced mouse ear angiogenesis model. To evaluate the antitumor effects of the vectors, immunodeficient mice were pretreated with rAAV-3TSR or rAAV-endostatin and received orthotopic implantation of cancer cells into the pancreas. To mimic clinical situations, mice bearing pancreatic tumors were treated with intratumoral injection of rAAV-3TSR or rAAV-endostatin. RESULTS: rAAV-mediated i.m. gene delivery resulted in expression of the transgene in skeletal muscle with inhibition of VEGF-induced angiogenesis at a distant site (the ear). Local delivery of the vectors into the mouse ear also inhibited VEGF-induced ear angiogenesis. Pretreatment of mice with i.m. or intrasplenic injection of rAAV-endostatin or rAAV-3TSR significantly inhibited tumor growth. A single intratumoral injection of each vector also significantly decreased the volume of large established pancreatic tumors. Tumor microvessel density was significantly decreased in each treatment group and was well correlated with tumor volume reduction. Greater antiangiogenic and antitumor effects were achieved when rAAV-3TSR and rAAV-endostatin were combined. CONCLUSIONS: rAAV-mediated 3TSR and endostatin gene therapy showed both localized and systemic therapeutic effects against angiogenesis and tumor growth and may provide promise for patients with pancreatic cancer.

Authors
Zhang, X; Xu, J; Lawler, J; Terwilliger, E; Parangi, S
MLA Citation
Zhang, X, Xu, J, Lawler, J, Terwilliger, E, and Parangi, S. "Adeno-associated virus-mediated antiangiogenic gene therapy with thrombospondin-1 type 1 repeats and endostatin." Clinical cancer research : an official journal of the American Association for Cancer Research 13.13 (July 2007): 3968-3976.
PMID
17606731
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
13
Issue
13
Publish Date
2007
Start Page
3968
End Page
3976
DOI
10.1158/1078-0432.ccr-07-0245

Continuous administration of the three thrombospondin-1 type 1 repeats recombinant protein improves the potency of therapy in an orthotopic human pancreatic cancer model.

Thrombospondin-1 is one of most important natural angiogenic inhibitors. The three thrombospondin-1 type 1 repeats (3TSR), an anti-angiogenic domain of thrombospondin-1, is a promising novel agent for anti-angiogenic treatment. In the present study, we showed 3TSR was biologically stable at least for 7 days in mini-osmotic pumps in vivo, and continuous administration of 3TSR decreased the dosage and improved the potency of therapy in an orthotopic pancreatic cancer model. By using different dosage and delivery routes, we proved that the anti-tumor efficacy of 3TSR was correlated with its anti-angiogenic efficacy. 3TSR treatment also decreased tumor vessel patency and blood flow. The results indicate the advantage of continuous administration of angiogenic inhibitors and provide rationale for using such delivery methods for cancer treatment.

Authors
Zhang, X; Connolly, C; Duquette, M; Lawler, J; Parangi, S
MLA Citation
Zhang, X, Connolly, C, Duquette, M, Lawler, J, and Parangi, S. "Continuous administration of the three thrombospondin-1 type 1 repeats recombinant protein improves the potency of therapy in an orthotopic human pancreatic cancer model." Cancer letters 247.1 (March 2007): 143-149.
PMID
16757110
Source
epmc
Published In
Cancer Letters
Volume
247
Issue
1
Publish Date
2007
Start Page
143
End Page
149
DOI
10.1016/j.canlet.2006.04.003

Antiangiogenic treatment with three thrombospondin-1 type 1 repeats versus gemcitabine in an orthotopic human pancreatic cancer model.

In this study, we investigated the antitumor efficacy of thrombospondin-1 three type 1 repeats (3TSR), the antiangiogenic domain of thrombospondin-1, in comparison and in combination with gemcitabine, in an orthotopic pancreatic cancer model.Human pancreatic cancer cells were injected into the pancreas of severe combined immunodeficient mice. The animals were treated with 3TSR, gemcitabine, 3TSR plus gemcitabine, or vehicle for 3 weeks. Subsequently, the effects of 3TSR and/or gemcitabine on tumor growth, tumor necrosis, microvessel density, cancer cell proliferation, apoptosis, and endothelial cell apoptosis were analyzed.After 3 weeks of treatment, 3TSR reduced tumor volume by 65%, and gemcitabine by 84%. Tumor volume was not statistically different between gemcitabine group and combinatorial treatment group. Extensive necrotic areas were observed in tumors from 3TSR-treated mice, whereas tumors from gemcitabine and combinatorially treated mice were less necrotic than control tumors. 3TSR reduced tumor microvessel density and increased tumor blood vessel endothelial cell apoptosis. In contrast, gemcitabine induced apoptosis and inhibited proliferation of cancer cells.3TSR, the antiangiogenic domain of thrombospondin-1, showed comparable antitumor efficacy to gemcitabine in a human pancreatic cancer orthotopic mouse model. No synergistic effect was found when the two drugs were combined and possible reasons are discussed in detail. A delicate balance between normalization and excessive regression of tumor vasculature is important when initiating alternative combinatorial regimens for treatment of patients with pancreatic cancer.

Authors
Zhang, X; Galardi, E; Duquette, M; Lawler, J; Parangi, S
MLA Citation
Zhang, X, Galardi, E, Duquette, M, Lawler, J, and Parangi, S. "Antiangiogenic treatment with three thrombospondin-1 type 1 repeats versus gemcitabine in an orthotopic human pancreatic cancer model." Clinical cancer research : an official journal of the American Association for Cancer Research 11.15 (August 2005): 5622-5630.
PMID
16061881
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
11
Issue
15
Publish Date
2005
Start Page
5622
End Page
5630
DOI
10.1158/1078-0432.ccr-05-0459

Antiangiogenic treatment with the three thrombospondin-1 type 1 repeats recombinant protein in an orthotopic human pancreatic cancer model.

This study investigates the antiangiogenesis and antitumor efficacy of a recombinant protein composed of the three type 1 repeats (3TSR) of thrombospondin-1 in an orthotopic human pancreatic cancer model and provides useful preclinical data for pancreatic cancer treatment.Human pancreatic cancer cells (AsPC-1) were injected into the pancreas of severe combined immunodeficient mice. The animals were treated with 3TSR (3 mg per kg per day) or PBS for 3 weeks. Subsequently, the effects of 3TSR on tumor growth, microvessel density, cancer cell proliferation, apoptosis, and endothelial cell apoptosis were analyzed. The in vitro effects of 3TSR on human pancreatic cancer cells were also studied.3TSR treatment significantly reduced angiogenesis and tumor growth of orthotopic pancreatic cancer. 3TSR-treated mice had a 69% reduction in tumor volume (316.6 +/- 79.3 versus 1,012.2 +/- 364.5 mm(3); P = 0.0001), and a significant increase in tumor necrotic area. After 3TSR treatment, both the vessel number and average microvessel size were significantly decreased, and microvessel density was decreased from 8.0% to 3.7% (P < 0.0001). The apoptotic rate of tumoral endothelial cells in 3TSR-treated tumors increased to 14.7% comparing to 4.2% in control tumors (P < 0.0001). 3TSR showed no direct effects on pancreatic cancer cell proliferation or apoptosis either in vivo or in vitro.3TSR, a domain of a natural occurring angiogenesis inhibitor, showed potent therapeutic effect in pancreatic cancer by inhibiting tumor angiogenesis and may prove to be a promising agent for clinical pancreatic cancer treatment.

Authors
Zhang, X; Galardi, E; Duquette, M; Delic, M; Lawler, J; Parangi, S
MLA Citation
Zhang, X, Galardi, E, Duquette, M, Delic, M, Lawler, J, and Parangi, S. "Antiangiogenic treatment with the three thrombospondin-1 type 1 repeats recombinant protein in an orthotopic human pancreatic cancer model." Clinical cancer research : an official journal of the American Association for Cancer Research 11.6 (March 2005): 2337-2344.
PMID
15788685
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
11
Issue
6
Publish Date
2005
Start Page
2337
End Page
2344
DOI
10.1158/1078-0432.ccr-04-1900
Show More