Research ArticleExperimental Studies

Establishment and Characterization of a Novel Xenograft Model of Human Gastrointestinal Stromal Tumor in Mice

MAKOTO MORIYAMA, YUTAKA SHIMADA, TAKUYA NAGATA, TETSUYA OMURA, SHINICHI SEKINE, KOSHI MATSUI, ISAKU YOSHIOKA, TOMOYUKI OKUMURA, SHIGEAKI SAWADA, TORU YOSHIDA and KAZUHIRO TSUKADA
Anticancer Research January 2013, 33 (1) 175-181;

Abstract

Background: The clinical outcome of gastrointestinal stromal tumor (GIST) has been improved by the introduction of molecular-targeting drugs. However, resistance to these drugs appears during the course of treatment. The aim of this study was to establish and characterize a human xenograft model of GIST. Materials and Methods: GIST tissue from a patient with esophageal GIST was implanted under the skin of a NOD-SCID mouse. The tumor became successfully engrafted and we investigated the effects of imatinib and sunitinib on this model. KIT mutation was investigated by complementary DNA analysis, and c-KIT (CD117) expression was evaluated by immunohistological staining. Results: cDNA analysis of the tumor revealed a KIT mutation in exon 11. c-KIT expression was observed in each passaged tumor. Both imatinib and sunitinib significantly reduced the size of the xenograft tumor. Conclusion: We established a novel xenograft model of human GIST in mice. This xenograft model may be useful for studying GIST.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract and originates from the interstitial cells of Cajal (1, 2). The majority of GISTs have mutations in their thymidine kinase (TK) receptor (KIT) genes, usually in the regions that encode the auto-regulatory domains of TK. These mutations predominantly occur in exons 11 (66%) and 9 (10-18%) of the KIT gene (3). GISTs with mutations in exons 13 or 17 of the KIT gene are less common (3). In addition, a few GISTs harbor mutations in the gene for platelet-derived growth factor receptor-alpha (PDGFRA), which is related to the TK gene (3,4). Activating KIT or PDGFRA mutations have been defined as the underlying pathogenic events in GIST development.

Surgery is currently the first-line treatment for patients with primary resectable GIST. However, increases in our understanding of the molecular pathophysiology of GIST have led to the development of agents that target and selectively inhibit TK activity (5). For example, the suppression of signal transduction pathways in GIST cells with the TK inhibitors imatinib resulted in reduced cell proliferation and the induction of apoptosis (6). The introduction of these new targeted drugs has significantly improved the prospects of patients with locally advanced or metastatic GIST. Imatinib is currently the standard, first-line treatment for these patients and shows improved overall survival by four years, compared with conventional chemotherapeutic treatment (7).

However, the majority of patients for whom imatinib is initially effective, eventually develop resistance to the drug. Furthermore, about 19% of patients with GIST do not respond to imatinib, and another 5% develop unacceptable adverse effects (8). Secondary or late resistance develops after a median of almost two years' treatment (9). During the past few years, other signal transduction inhibitors such as sunitinib, nilotinib, and sorafenib have been developed (8, 10, 11). Out of these inhibitors, only sunitinib has been used in clinical practice as a second-line treatment for patients with imatinib-resistant GIST (8).

The toxicity and safety of imatinib and sunitinib have been confirmed, but they have not been confirmed to have direct antitumor effects in vivo. In a previous study, a human GIST cell line was subcutaneously implanted into mice to establish a human GIST xenograft mouse model, but the effects of TK inhibitors on this model were not examined (12).

The present study describes the establishment of a novel xenograft mouse model of human GIST, as well as its histology and immunohistology, and the effects of TK inhibitors on this model.

Figure 1.
Figure 1.

Gross findings of the resected specimen. A solid, firm, elastic, ulcerated tumor measuring 9.0×6.8×3.5 cm in size was completely excised with the esophagus. The white arrow indicates the border of the Gastrointestinal stromal tumor.

Materials and Methods

Patient history. A 72-year-old man was diagnosed with esophageal GIST by gastrointestinal endoscopy and biopsy. The GIST was located in the lower thoracic esophagus and had invaded into the stomach. In order to resect the tumor safely and prevent micrometastasis, the patient was treated with imatinib at a daily dose of 400 mg. One month after the chemotherapy, a marked reduction in the size of the tumor was observed; however, the continuous administration of imatinib for a further two months did not result in further reduction in tumor size. Thus, we performed subtotal esophagectomy through a right thoracotomy and reconstructed the esophagus with a gastric tube (Figure 1). Adjuvant imatinib treatment was planned, which the patient received for approximately three weeks. However, the patient stopped taking imatinib as he developed severe appetite loss. Ten months after the operation, a recurrent liver tumor was observed.

Establishment of the GIST xenograft. We aimed to develop a novel GIST xenograft model by transplanting human GIST xenograft tissue into a female non-obese diabetic (NOD) CB17-Prkdc(SCID)/J (NOD-SCID) mouse (Charles River Laboratories, Yokohama, Japan). Written informed consent for the use of resected specimens for research was obtained from the patient described above before surgery. The study was approved from the Institutional Review Board of the University of Toyama (approval number #22-11 & #Med-57). The GIST tissue in the surgical specimen was cut into small pieces and subcutaneously inserted into the right and left flanks of the NOD-SCID mouse. The xenograft tumor tissue had become successfully engrafted approximately four months after its transplantation (Figure 2). After eight months of transplantation, the xenografted tissue was subsequently transferred into 4-6 week-old female CAnN.Cg-Foxn1nu/CrlCrlj (BALB/c) nude mice (Charles River Laboratories) (n=3).

Figure 2.
Figure 2.

Gastrointestinal stromal tumor tissue in the surgical specimen was cut into small pieces and subcutaneously inserted into the right and left flanks of a NOD-SCID mouse. It had become successfully engrafted by eight months after its transplantation.

Tumor growth curve. Tumor volume was measured weekly in xenografted mice with external calipers. Individual tumor volumes were calculated using the modified ellipsoid formula: tumor volume=1/2(a×b2), where a is the longest longitudinal diameter (length) and b is the longest transverse diameter (width) of the xenograft.

Cell culture. The xenograft tissue was surgically removed from growth tumor of the xenograft mouse was mechanically minced with sharp scissors. Then, the minced tumor were digested by collagenase (Invitrogen Co, Grand Island, NY, USA) and dispase (Invitrogen Co, Grand Island, NY, USA) solution (1:1) for 90 min at 37°C on a shaker. Cells were initially cultured in Dulbecco's Modified Eagle's medium + HAM's F12 medium (Wako, Osaka Japan), supplemented with 10% fetal bovine serum containing antibiotics (GIBCO, Grand Island, NY, USA) at 4°C. The cells were maintained in humidified incubators at 37°C in an atmosphere of 5% CO2 and 95% air.

Agents. Imatinib mesylate (S1026) was purchased from Selleck Chemicals LLC (Houston, TX, USA), and sunitinib malate (PZ0012) was purchased from Sigma-Aldrich Japan (Tokyo, Japan). These agents were dissolved in DMSO, and diluted in PBS. Control agent was adjusted by DMSO and PBS. For each treatment, a dose of imatinib at 100 mg/kg twice daily, a dose of sunitinib at 40 mg/kg once daily and PBS as control into 4 to 5 nude mice by oral gavage.

Mutation screening. To analyze the mutations in the KIT and PDGFRA genes, DNA was extracted from culture cells using the QIAamp DNA mini kit (Qiagen Inc, Valencia, CA, USA). DNA sample was amplified with polymerase chain reaction (PCR) for 40 cycles. After purification of the PCR products, mutation screening of exons 9, 11, 13, and 17 of KIT and exon 12, 14, and 18 of PDGFRA was performed by DNA direct sequencing analysis. The primers were obtained from FALCO biosystems Ltd (#7530, #7533, #7646, Kyoto, Japan).

Figure 3.
Figure 3.

A: Histopathological findings of an endoscopic biopsy sample obtained before imatinib treatment. Histologically, mitotic spindle cells were observed. Immunohistochemical analysis detected c-KIT- and MIB-1-positive cells. B: Histopathological findings of the resected specimen. Histologically, spindle cells were observed, a few of which were mitotic. Immunohistochemical analysis revealed c-KIT- and MIB-1-positive cells. However, there were fewer c-KIT- and MIB-1-positive cells in the resected specimen than in the biopsy sample.

Immunohistochemistry. Immunohistochemical analysis of c-KIT expression was carried out using paraffin-embedded sections of the GIST xenograft tumors from fifth-passage BALB/c nude mice that were sacrificed by isoflurane. We used a rabbit polyclonal c-KIT antibody (A4502; Dako, Glostrup, Denmark) at a dilution of 1:100, Envision+dual link system-HRP (K4061, DAKO, Glostrup, Denmark) method.

Statistical analysis. The results are expressed as mean±standard error of the mean. Statistical significance was calculated by repeated measurements one-way analysis of variance (ANOVA) using JMP9 (SAS Institute Inc, Cary, NC, USA). Statistical significance is a comparison of the each entire graphs between zero week and four or five weeks. Any p-value is comparison of control group versus treatment group.

Figure 4.
Figure 4.

A: The findings of a fifth-passage xenograft mouse model of human gastrointestinal stromal tumor. B: The tumor xenograft displayed spindle cells, and immunohistochemical staining detected c-KIT positivity. It was possible to culture the xenograft tissue.

Results

Evaluation of clinical samples. An endoscopic biopsy sample obtained before the patient was treated with imatinib revealed the presence of spindle cells, and immunohistochemical staining detected c-KIT- and Ki-67 (MIB-1)-positive cells (Figure 3A). After imatinib treatment, the surgical specimen displayed reduced c-KIT expression compared with the biopsy sample (Figure 3B).

Model establishment and tumor characteristics. The tumor doubling time for the seventh passage was found to be approximately 3.4 weeks. We subcultured the xenografted tissue into nude mice every four to six months (Figure 4A). The xenograft tissue contained spindle cells, and immunohistochemical staining detected c-KIT. It was possible to culture the xenograft tissue (Figure 4B); however, it was only possible to subculture it for a short period, i.e. until approximately the fifth passage. We also found that the c-KIT expression of the tumor tissue was reduced with each passage. Complementary DNA analysis of the cultured cells revealed a 1690del6 mutation in exon 11 (W557_K558del) of the c-KIT gene (Figure 5).

Figure 5.
Figure 5.

Complementary DNA analysis of the tumor revealed a 1690del6 mutation in exon 11 (W557_K558del) of the c-KIT gene.

Tumor growth inhibition after imatinib treatment. We treated the mice xenografted with fourth passage GIST for two weeks with imatinib (100 mg/kg twice daily) or PBS (control) (imatinib: n=3, control: n=2) and observed the mice for a further six weeks. Imatinib treatment produced a greater reduction in tumor size than did PBS treatment (p=0.134). However, the tumors grew again after the imatinib treatment was stopped. After two weeks of treatment and six weeks of observation, we treated the regrowing tumors with imatinib, which produced further re-ductions in their size (Figure 6).

Next, we treated the mice xenografted with sixth passage GIST xenografted mice with imatinib for two weeks (imatinib: n=5, control: n=5) and examined them for a further three weeks. Imatinib treatment produced a significantly greater reduction in tumor size than did PBS treatment (p=0.0384) (Figure 7).

Tumor growth inhibition after sunitinib treatment. We treated the mice xenografted with sixth passage GIST with sunitinib (40 mg/kg once daily) or PBS (control) for two weeks (sunitinib: n=4, control: n=4) and then examined the mice for a further two weeks. Sunitinib treatment produced a significantly greater reduction in tumor size than did PBS treatment (p=0.0265) (Figure 8). However, the tumors began to grow again after the sunitinib treatment was stopped, as was found during the imatinib treatment.

Figure 6.
Figure 6.

In fourth-passage xenograft mice, imatinib treatment produced a significantly greater reduction in xenograft tumor size than did treatment with phosphate-buffered saline (control). However, the xenograft tumors grew again after the imatinib treatment was stopped. We subsequently treated the re-growing tumors with imatinib, which resulted in a further reduction in their size.

Immunohistochemical analysis. Strong c-KIT expression was detected in the xenografted tumor tissue prior to imatinib treatment. However, c-KIT expression was reduced by imatinib treatment. These results were very similar to those observed in the patient with GIST (Figure 9).

Discussion

Immunodeficient mice have been used for various in vivo studies of human tissues, often as in vivo tumor models that have been implanted with in vitro cultured tumor cell lines (13-16). However, many of these models do not display the same proliferation patterns and structures as the original tissue and tend to be poorly-differentiated; thus, the engraftment of surgically excised human tumor tissue into immunodeficient mice is an alternative model that better preserves the characteristics of the original tumor (13-16). In addition, established tissue lines derived from such tissues could be used on demand and would provide a powerful tool for studying tumor biology. The most commonly cited benefit of patient-derived xenograft models is that they retain the intratumoral heterogeneity and histological characteristics seen in primary tumors (17, 18). Here, we established a novel xenograft mouse model of human GIST that did not involve the use of in vitro-cultured cells.

Figure 7.
Figure 7.

In sixth-passsage xenograft mice, imatinib treatment produced a significantly greater reduction in xenograft tumor size than did treatment with phosphate-buffered saline (control) (p=0.0384*). Statistical significance was a comparison of the each-entire graphs between zero of the week and five weeks, and was calculated by repeated measurement analysis of variance (ANOVA).

There are a few reports about xenograft models of GIST that were established without in vitro culturing (12, 19, 20). Our model mimicked the clinical condition of the patient from whom the original GIST was obtained. Both the original GIST and the GIST xenograft were sensitive to imatinib. However, the GIST xenograft was grown in the absence of imatinib. In addition, in immunohistochemical analysis, the c-KIT expression of the xenograft tissue was found to be similar to that of the clinical specimen after imatinib treatment. Furthermore, the c-KIT expression of both the clinical specimen and the xenograft tissue were reduced by imatinib treatment. To our knowledge, there are no reports about GIST xenograft mouse models that mimicked clinical cases. Therefore, our xenograft model is a very valuable tool for studying GIST.

The surgical specimen displayed lower c-KIT expression than the biopsy sample obtained prior to imatinib treatment, and a previous report found that GIST stem cells displayed low c-KIT expression and suggested that low c-KIT expression aids the successful engraftment of GIST into NOD-SCID mice (21). Thus, we consider that implanting the surgical specimen into the NOD-SCID mouse after the original tumor had been treated with imatinib aided in the successful establishment of our GIST model, as it might have increased the xenograft's growth potential. Furthermore, we think that it is important to trim the specimen to an appropriate size, carefully observe it and patiently wait.

Figure 8.
Figure 8.

In sixth passage xenograft mice, sunitinib treatment produced a significantly greater reduction in xenograft tumor size than did treatment with phosphate-buffered saline (control) (p=0.0265*). Statistical significance was a comparison of the each entire graphs between zero week and four weeks, and was calculated by repeated measures analysis of variance (ANOVA).

Figure 9.
Figure 9.

Immunohistochemical analysis revealed that the c-KIT expression of the xenograft tumor was reduced by imatinib treatment, which was very similar to the findings obtained in the clinical case.

Regarding the culturing of the xenograft tumor tissue, we found that it was impossible to subculture it for a long period. However, it was possible to subculture it for a short period, i.e. until approximately the fifth passage. We also found that the c-KIT expression of the tumor tissue was reduced with each passage. On the other hands, c-KIT expression-negative cells retained KIT mutation in exon 11. Thus, a few passage cultured cells may be useful for GIST study. Mutations in exon 11 of the c-KIT gene are also the most common mutations in GIST; thus, our model, which displayed exon 11 mutation, might become a commonly used tool for studying GIST.

Although imatinib has been shown to be effective as a first-line treatment for GIST, most patients will eventually develop imatinib resistance (4, 8, 22). Such resistance can develop through various mechanisms, the most common being secondary KIT mutations such as in exon 17 in clonally expanded cancer cells (23, 24). Although the xenograft established in the present study only harbored exon 11 mutation, the continuous administration of imatinib might induce secondary KIT mutations.

The established GIST xenograft model could be used to study the resistance mechanisms of GIST, as well as combination and targeted therapies for GIST. It could also be used to develop new more specific biomarkers of GIST. However, the development of patient-derived xenograft models introduces logistical challenges, for example, it will often be necessary to freeze and revitalize tumor tissues after months on years of storage. Close coordination with surgeons and the implantation of specimens as rapidly as possible after their devascularization improves engraftment rates and might be critical for tumors with low engraftment rates.

In conclusion, a xenograft mouse model of human GIST was established from a human GIST. The xenograft model can be used to test new drugs such as TK inhibitors and other agents being developed to circumvent treatment resistance.

Acknowledgements

We thank Dr Mika Kigawa, Center for the Advancement of Medical Training, Toyama University Hospital (Toyama, Japan) for statistical analysis suggestions. We received research grants from the Japanese Ministry of Education, Culture, Sports, Science, and Technology (MEXT/JSPS KAKENHI Grant Number B:23390320). We also received a research grant from the Japan Society for the Promotion of Science (JSPS) Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program). The Authors declare that they have no conflicts of interest in regard to this study.

  • Received November 6, 2012.
  • Revision received November 21, 2012.
  • Accepted November 22, 2012.

References

  1. ↵
    1. DeMatteo RP,
    2. Lewis JJ,
    3. Leung D,
    4. Mudan SS,
    5. Woodruff JM,
    6. Brennan MF
    : Two hundred gastrointestinal stromal tumors: Recurrence patterns and prognostic factors for survival. Ann Surg 231: 51-58, 2000.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Fletcher CD,
    2. Berman JJ,
    3. Corless C,
    4. Gorstein F,
    5. Lasota J,
    6. Longley B J,
    7. Miettinen M,
    8. O'Leary TJ,
    9. Remotti H,
    10. Rubin BP,
    11. Shmookler B,
    12. Sobin LH,
    13. Weiss SW
    : Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol 33: 459-465, 2002.
    OpenUrlCrossRefPubMed
  3. ↵
    1. Tornillo L,
    2. Terracciano LM
    : An update on molecular genetics of gastrointestinal stromal tumours. J Clin Pathol 59: 557-563, 2006.
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Heinrich MC,
    2. Corless CL,
    3. Demetri GD,
    4. Blanke CD,
    5. von MM,
    6. Joensuu H,
    7. McGreevey LS,
    8. Chen CJ,
    9. Van den Abbeele AD,
    10. Druker BJ,
    11. Kiese B,
    12. Eisenberg B,
    13. Roberts PJ,
    14. Singer S,
    15. Fletcher CD,
    16. Silberman S,
    17. Dimitrijevic S,
    18. Fletcher JA
    : Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21: 4342-4349, 2003.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. DeMatteo RP,
    2. Heinrich MC,
    3. El-Rifai WM,
    4. Demetri G
    : Clinical management of gastrointestinal stromal tumors: Before and after STI-571. Hum Pathol 33: 466-477, 2002.
    OpenUrlCrossRefPubMed
  6. ↵
    1. Tuveson DA,
    2. Willis NA,
    3. Jacks T,
    4. Griffin JD,
    5. Singer S,
    6. Fletcher CD,
    7. Fletcher JA,
    8. Demetri GD
    : STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: Biological and clinical implications. Oncogene 20: 5054-5058, 2001.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Joensuu H
    : Gastrointestinal stromal tumor (GIST). Ann Oncol 17(Suppl 10): 280-286, 2006.
    OpenUrl
  8. ↵
    1. Demetri GD,
    2. van Oosterom AT,
    3. Garrett CR,
    4. Blackstein ME,
    5. Shah MH,
    6. Verweij J,
    7. McArthur G,
    8. Judson IR,
    9. Heinrich MC,
    10. Morgan JA,
    11. Desai J,
    12. Fletcher CD,
    13. George S,
    14. Bello CL,
    15. Huang X,
    16. Baum CM,
    17. Casali PG
    : Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: A randomised controlled trial. Lancet 368: 1329-1338, 2006.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Blanke C
    : Current and future management of GIST. Clin Adv Hematol Oncol 4: 582-583, 2006.
    OpenUrlPubMed
  10. ↵
    1. Deremer DL,
    2. Ustun C,
    3. Natarajan K
    : Nilotinib: A second-generation tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia. Clin Ther 30: 1956-1975, 2008.
    OpenUrlCrossRefPubMed
  11. ↵
    1. Braconi C,
    2. Bracci R,
    3. Cellerino R
    : Molecular targets in gastrointestinal stromal tumors (GIST) therapy. Curr Cancer Drug Targets 8: 359-366, 2008.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Revheim ME,
    2. Seierstad T,
    3. Berner JM,
    4. Bruland OS,
    5. Røe K,
    6. Ohnstad HO,
    7. Bjerkehagen B,
    8. Bach-Gansmo T
    : Establishment and characterization of a human gastrointestinal stromal tumour (GIST) xenograft in athymic nude mice. Anticancer Res 29: 4331-4336, 2009.
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Mueller BM,
    2. Reisfeld RA
    : Potential of the SCID mouse as a host for human tumors. Cancer Metastasis Rev 10: 193-200, 1991.
    OpenUrlCrossRefPubMed
    1. Williams SS,
    2. Alosco TR,
    3. Croy BA,
    4. Bankert RB
    . The study of human neoplastic disease in severe combined immunodeficient mice. Lab Anim Sci 43: 139-146, 1993.
    OpenUrlPubMed
    1. Bankert RB,
    2. Hess SD,
    3. Egilmez NK
    : SCID mouse models to study human cancer pathogenesis and approaches to therapy: Potential, limitations, and future directions. Front Biosci 7: 44-62, 2002.
    OpenUrl
  16. ↵
    1. Sausville EA,
    2. Burger AM
    : Contributions of human tumor xenografts to anticancer drug development. Cancer Res 66: 3351-3354, 2006.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Julien S,
    2. Merino-Trigo A,
    3. Lacroix L,
    4. Pocard M,
    5. Goéré D,
    6. Mariani P,
    7. Landron S,
    8. Bigot L,
    9. Nemati F,
    10. Dartigues P,
    11. Weiswald LB,
    12. Lantuas D,
    13. Morgand L,
    14. Pham E,
    15. Gonin P,
    16. Dangles-Marie V,
    17. Job B,
    18. Dessen P,
    19. Bruno A,
    20. Pierré A,
    21. De Thé H,
    22. Soliman H,
    23. Nunes M,
    24. Lardier G,
    25. Calvet L,
    26. Demers B,
    27. Prévost G,
    28. Vrignaud P,
    29. Roman-Roman S,
    30. Duchamp O,
    31. Berthet C
    : Characterization of a large panel of patient-derived tumor xenografts representing the clinical heterogeneity of human colorectal cancer. Clin Cancer Res 18(19): 5314-5328, 2012.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Kopetz S,
    2. Lemos R,
    3. Powis G
    : The promise of patient-derived xenografts: The best laid plans of mice and men. Clin Cancer Res 18(19): 5160-5262, 2012.
    OpenUrlAbstract/FREE Full Text
  19. ↵
    1. Prenen H,
    2. Deroose C,
    3. Vermaelen P,
    4. Sciot R,
    5. Debiec-Rychter M,
    6. Stroobants S,
    7. Mortelmans L,
    8. Schöffski P,
    9. Van Oosterom A
    : Establishment of a mouse gastrointestinal stromal tumour model and evaluation of response to imatinib by small animal positron emission tomography. Anticancer Res 26: 1247-1252, 2006.
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Huynh H,
    2. Lee JW,
    3. Chow PK,
    4. Ngo VC,
    5. Lew GB,
    6. Lam IW,
    7. Ong HS,
    8. Chung A,
    9. Soo KC
    : Sorafenib induces growth suppression in mouse models of gastrointestinal stromal tumor. Mol Cancer Ther 8: 152-159, 2009.
    OpenUrlAbstract/FREE Full Text
  21. ↵
    1. Bardsley MR,
    2. Horváth VJ,
    3. Asuzu DT,
    4. Lorincz A,
    5. Redelman D,
    6. Hayashi Y,
    7. Popko LN,
    8. Young DL,
    9. Lomberk GA,
    10. Urrutia RA,
    11. Farrugia G,
    12. Rubin BP,
    13. Ordog T
    : Kitlow stem cells cause resistance to Kit/platelet-derived growth factor alpha inhibitors in murine gastrointestinal stromal tumors. Gastroenterology 139: 942-952, 2010.
    OpenUrlCrossRefPubMed
  22. ↵
    1. Joensuu H
    : Sunitinib for imatinib-resistant GIST. Lancet 368: 1303-1304, 2006.
    OpenUrlPubMed
  23. ↵
    1. Liegl B,
    2. Kepten I,
    3. Le C,
    4. Zhu M,
    5. Demetri GD,
    6. Heinrich MC,
    7. Fletcher CD,
    8. Corless CL,
    9. Fletcher JA
    : Heterogeneity of kinase inhibitor resistance mechanisms in GIST. J Pathol 216: 64-74, 2008.
    OpenUrlCrossRefPubMed
  24. ↵
    1. Heinrich MC,
    2. Corless CL,
    3. Blanke CD,
    4. Demetri GD,
    5. Joensuu H,
    6. Roberts PJ,
    7. Eisenberg BL,
    8. von Mehren M,
    9. Fletcher CD,
    10. Sandau K,
    11. McDougall K,
    12. Ou WB,
    13. Chen CJ,
    14. Fletcher JA
    : Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 24: 4764-4774, 2006.
    OpenUrlAbstract/FREE Full Text
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Establishment and Characterization of a Novel Xenograft Model of Human Gastrointestinal Stromal Tumor in Mice
MAKOTO MORIYAMA, YUTAKA SHIMADA, TAKUYA NAGATA, TETSUYA OMURA, SHINICHI SEKINE, KOSHI MATSUI, ISAKU YOSHIOKA, TOMOYUKI OKUMURA, SHIGEAKI SAWADA, TORU YOSHIDA, KAZUHIRO TSUKADA
Anticancer Research Jan 2013, 33 (1) 175-181;
Twitter logo Facebook logo Mendeley logo

Jump to section

Keywords