Differential response to EGFR- and VEGF-targeted therapies in patient-derived tumor tissue xenograft models of colon carcinoma and related metastases

Jin,Ketao; Lan,Huanrong; Cao,Feilin; Han,Na; Xu,Zhenzhen; Li,Guangliang; He,Kuifeng; Teng,Lisong

doi:10.3892/ijo.2012.1469

Differential response to EGFR- and VEGF-targeted therapies in patient-derived tumor tissue xenograft models of colon carcinoma and related metastases

Authors:
- Ketao Jin
- Huanrong Lan
- Feilin Cao
- Na Han
- Zhenzhen Xu
- Guangliang Li
- Kuifeng He
- Lisong Teng
View Affiliations

Affiliations: Department of Surgical Oncology, Taizhou Hospital, Wenzhou Medical College, Linhai, Zhejiang, P.R. China, Department of Gynecology and Obstetrics, Taizhou Hospital, Wenzhou Medical College, Linhai, Zhejiang, P.R. China, Cancer Chemotherapy Center, Zhejiang Cancer Hospital, Zhejiang University of Chinese Medicine, Hangzhou, Zhejiang, P.R. China, Department of Surgical Oncology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China, Department of Surgical Oncology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
Published online on: May 10, 2012 https://doi.org/10.3892/ijo.2012.1469
Pages: 583-588

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Heterogeneity in primary tumors and related metastases may result in failure of antitumor therapies, particularly in targeted therapies for the treatment of cancer. In this study, patient-derived tumor tissue (PDTT) xenograft models of colon carcinoma with lymphatic and hepatic metastases were used to evaluate the response to EGFR- and VEGF-targeted therapies. Our results showed that primary colon carcinoma and its corresponding lymphatic and hepatic metastases have a different response rate to anti-EGFR (cetuximab) and anti-VEGF (bevacizumab) therapies. However, the underlying mechanism of these types of phenomenon is still unclear. To investigate whether such phenomena may result from the heterogeneity in primary colon carcinoma and related metastases, we compared the expression levels of cell signaling pathway proteins using immunohistochemical staining and western blotting, and the gene status of KRAS using pyrosequencing in the same primary colon carcinoma and its corresponding lymphatic and hepatic metastatic tissues which were used for establishing the PDTT xenograft models. Our results showed that the expression levels of EGFR, VEGF, Akt/pAkt, ERK/pERK, MAPK/pMAPK, and mTOR/pmTOR were different in primary colon carcinoma and matched lymphatic and hepatic metastases although the KRAS gene status in all cases was wild-type. Our results indicate that the heterogeneity in primary colon carcinoma and its corresponding lymphatic and hepatic metastases may result in differences in the response to dual-inhibition of EGFR and VEGF.

View Figures

View References

1	Jin KT, He KF, Teng F, Han N, Li GL, Xu ZZ and Teng LS: Heterogeneity in primary tumors and corresponding metastases: could it provide us with any hints to personalize cancer therapy? Pers Med. 8:175–182. 2011. View Article : Google Scholar
2	Gong Y, Booser DJ and Sneige N: Comparison of HER-2 status determined by fluorescence in situ hybridization in primary and metastatic breast carcinoma. Cancer. 103:1763–1769. 2005. View Article : Google Scholar : PubMed/NCBI
3	Gancberg D, Di Leo A, Cardoso F, Rouas G, Pedrocchi M, Paesmans M, Verhest A, Bernard-Marty C, Piccart MJ and Larsimont D: Comparison of HER-2 status between primary breast cancer and corresponding distant metastatic sites. Ann Oncol. 13:1036–1043. 2002. View Article : Google Scholar : PubMed/NCBI
4	Regitnig P, Schippinger W, Lindbauer M, Samonigg H and Lax SF: Change of HER-2/neu status in a subset of distant metastases from breast carcinomas. J Pathol. 203:918–926. 2004. View Article : Google Scholar : PubMed/NCBI
5	Bozzetti C, Personeni N, Nizzoli R, Guazzi A, Flora M, Bassano C, Negri F, Martella E, Naldi N, Franciosi V and Cascinu S: HER-2/neu amplification by fluorescence in situ hybridization in cytologic samples from distant metastatic sites of breast carcinoma. Cancer. 99:310–315. 2003. View Article : Google Scholar : PubMed/NCBI
6	Tanner M, Järvinen P and Isola J: Amplification of HER-2/neu and topoisomerase IIalpha in primary and metastatic breast cancer. Cancer Res. 61:5345–5348. 2001.PubMed/NCBI
7	Tapia C, Savic S, Wagner U, et al: HER2 gene status in primary breast cancers and matched distant metastases. Breast Cancer Res. 9:R312007. View Article : Google Scholar : PubMed/NCBI
8	Akcakanat A, Sahin A, Shaye AN, Velasco MA and Meric-Bernstam F: Comparison of Akt/mTOR signaling in primary breast tumors and matched distant metastases. Cancer. 112:2352–2358. 2008. View Article : Google Scholar : PubMed/NCBI
9	Wu JM, Fackler MJ, Halushka MK, et al: Heterogeneity of breast cancer metastases: comparison of therapeutic target expression and promoter methylation between primary tumors and their multifocal metastases. Clin Cancer Res. 14:1938–1946. 2008. View Article : Google Scholar
10	Baldus SE, Schaefer KL, Engers R, Hartleb D, Stoecklein NH and Gabbert HE: Prevalence and heterogeneity of KRAS, BRAF, and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases. Clin Cancer Res. 16:790–799. 2010. View Article : Google Scholar : PubMed/NCBI
11	Molinari F, Martin V, Saletti P, De Dosso S, Spitale A, Camponovo A, Bordoni A, Crippa S, Mazzucchelli L and Frattini M: Differing deregulation of EGFR and downstream proteins in primary colorectal cancer and related metastatic sites may be clinically relevant. Br J Cancer. 100:1087–1094. 2009. View Article : Google Scholar : PubMed/NCBI
12	Scartozzi M, Bearzi I, Berardi R, Mandolesi A, Fabris G and Cascinu S: Epidermal growth factor receptor (EGFR) status in primary colorectal tumors does not correlate with EGFR expression in related metastatic sites: implications for treatment with EGFR-targeted monoclonal antibodies. J Clin Oncol. 22:4772–4778. 2004. View Article : Google Scholar
13	Scartozzi M, Bearzi I, Berardi R, Mandolesi A, Pierantoni C and Cascinu S: Epidermal growth factor receptor (EGFR) downstream signalling pathway in primary colorectal tumours and related metastatic sites: optimising EGFR-targeted treatment options. Br J Cancer. 97:92–97. 2007. View Article : Google Scholar
14	Sasatomi E, Finkelstein SD, Woods JD, Bakker A, Swalsky PA, Luketich JD, Fernando HC and Yousem SA: Comparison of accumulated allele loss between primary tumor and lymph node metastasis in stage II non-small cell lung carcinoma: implications for the timing of lymph node metastasis and prognostic value. Cancer Res. 62:2681–2689. 2002.PubMed/NCBI
15	Park S, Holmes-Tisch AJ, Cho EY, et al: Discordance of molecular biomarkers associated with epidermal growth factor receptor pathway between primary tumors and lymph node metastasis in non-small cell lung cancer. J Thorac Oncol. 4:809–815. 2009. View Article : Google Scholar : PubMed/NCBI
16	Li Z, Jin K, Lan H and Teng L: Heterogeneity in primary colorectal cancer and its corresponding metastases: a potential reason of EGFR-targeted therapy failure? Hepatogastroenterology. 58:411–416. 2011.PubMed/NCBI
17	Jin K, Li G, Cui B, et al: Assessment of a novel VEGF targeted agent using patient-derived tumor tissue xenograft models of colon carcinoma with lymphatic and hepatic metastases. PLoS One. 6:e283842011. View Article : Google Scholar : PubMed/NCBI
18	Jin K, Teng L, Shen Y, He K, Xu Z and Li G: Patient-derived human tumour tissue xenografts in immunodeficient mice: a systematic review. Clin Transl Oncol. 12:473–480. 2010. View Article : Google Scholar : PubMed/NCBI
19	Jin KT, He KF, Li GL and Teng LS: Personalized cancer therapy using a patient-derived tumor tissue xenograft model: a translational field worthy of exploring further? Pers Med. 7:597–606. 2010. View Article : Google Scholar
20	Jin K, He K, Han N, Li G, Wang H, Xu Z, Jiang H, Zhang J and Teng L: Establishment of a PDTT xenograft model of gastric carcinoma and its application in personalized therapeutic regimen selection. Hepatogastroenterology. 58:1814–1822. 2011.PubMed/NCBI
21	Ogino S, Kawasaki T, Brahmandam M, Yan L, Cantor M, Namgyal C, Mino-Kenudson M, Lauwers GY, Loda M and Fuchs CS: Sensitive sequencing method for KRAS mutation detection by Pyrosequencing. J Mol Diagn. 7:413–421. 2005. View Article : Google Scholar : PubMed/NCBI
22	Huynh H, Chow PK, Ooi LL and Soo KC: A possible role for insulin-like growth factor-binding protein-3 autocrine/paracrine loops in controlling hepatocellular carcinoma cell proliferation. Cell Growth Differ. 13:115–122. 2002.
23	Rubio-Viqueira B, Jimeno A, Cusatis G, et al: An in vivo platform for translational drug development in pancreatic cancer. Clin Cancer Res. 12:4652–4661. 2006. View Article : Google Scholar : PubMed/NCBI
24	Perez-Soler R, Kemp B, Wu QP, Mao L, Gomez J, Zeleniuch-Jacquotte A, Yee H, Lee JS, Jagirdar J and Ling YH: Response and determinants of sensitivity to paclitaxel in human non-small cell lung cancer tumors heterotransplanted in nude mice. Clin Cancer Res. 6:4932–4938. 2000.PubMed/NCBI
25	Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I and Van Cutsem E: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 351:337–345. 2004. View Article : Google Scholar : PubMed/NCBI
26	Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J and Mayer RJ: Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol. 22:1201–1208. 2004. View Article : Google Scholar : PubMed/NCBI
27	Amado RG, Wolf M, Peeters M, et al: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 26:1626–1634. 2008. View Article : Google Scholar : PubMed/NCBI
28	Cappuzzo F, Varella-Garcia M, Finocchiaro G, et al: Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients. Br J Cancer. 99:83–89. 2008. View Article : Google Scholar : PubMed/NCBI
29	Moroni M, Veronese S, Benvenuti S, Marrapese G, Sartore-Bianchi A, Di Nicolantonio F, Gambacorta M, Siena S and Bardelli A: Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to anti-EGFR treatment in colorectal cancer: a cohort study. Lancet Oncol. 6:279–286. 2005. View Article : Google Scholar : PubMed/NCBI
30	Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S, Siena S and Bardelli A: Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res. 67:2643–2648. 2007. View Article : Google Scholar
31	Foekens JA, Peters HA, Grebenchtchikov N, Look MP, Meijer-van Gelder ME, Geurts-Moespot A, van der Kwast TH, Sweep CG and Klijn JG: High tumor levels of vascular endothelial growth factor predict poor response to systemic therapy in advanced breast cancer. Cancer Res. 61:5407–5414. 2001.PubMed/NCBI
32	Gasparini G, Toi M, Gion M, et al: Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma. J Natl Cancer Inst. 89:139–147. 1997. View Article : Google Scholar : PubMed/NCBI
33	Konecny GE, Meng YG, Untch M, et al: Association between HER-2/neu and vascular endothelial growth factor expression predicts clinical outcome in primary breast cancer patients. Clin Cancer Res. 10:1706–1716. 2004. View Article : Google Scholar
34	Linderholm B, Grankvist K, Wilking N, Johansson M, Tavelin B and Henriksson R: Correlation of vascular endothelial growth factor content with recurrences, survival, and first relapse site in primary node-positive breast carcinoma after adjuvant treatment. J Clin Oncol. 18:1423–1431. 2000.
35	Gasparini G, Toi M, Miceli R, et al: Clinical relevance of vascular endothelial growth factor and thymidine phosphorylase in patients with node-positive breast cancer treated with either adjuvant chemotherapy or hormone therapy. Cancer J Sci Am. 5:101–111. 1999.
36	Verschraegen CF, Arias-Pulido H, Lee SJ, et al: Phase IB study of the combination of docetaxel, gemcitabine, and bevacizumab in patients with advanced or recurrent soft tissue sarcoma: the Axtell regimen. Ann Oncol. 23:785–790. 2012. View Article : Google Scholar : PubMed/NCBI