Tumor Microenvironment in Human Tumor Xenografted Mouse Models


  • Mariana Varna ESPCI Paris Tech, CNRS UMR 7587, Institut Langevin, 1 rue Jussieu, F-75005, Paris, France
  • Philippe Bertheau Université Paris Diderot, Sorbonne Paris Cité, F-75010 Paris, France
  • Luc G. Legrès Université Paris Diderot, Sorbonne Paris Cité, F-75010 Paris, France




Xenograft, tumor microenvironment, human tumor, immunodeficient mice, murine stroma, human stroma.


 Tumor microenvironment, known to exert regulatory functions on tumor cells, plays an important role when a human tumor is xenografted into immunodeficient mice. Primary human tumors xenografts represent a promising strategy to study new therapeutic efficacy or to understand the mechanisms implicated in tumor relapse. The development of xenografts is linked not only to the aggressivity of the tumor cells, but also to the tumor microenvironment. Tumor xenograft cell proliferation is dependent on microenvironment modifications such as angiogenesis and human blood vessel replacement, host immune cells and the presence of growth factors. The characterisation and a better knowledge of these factors allow for a more appropriate use of xenograft animal models in the evaluation of new antitumor treatments. In this review, we describe the different factors linked to the tumor microenvironment and their impact on the take rate when human tumors are xenografted into immunodeficient mice.


Witz IP and Levy-Nissenbaum O. The tumor microenvironment in the post-PAGET era. Cancer Lett 2006; 242: 1-10. http://dx.doi.org/10.1016/j.canlet.2005.12.005

Yron I, Wood TA, Jr., Spiess PJ, Rosenberg SA. In vitro growth of murine T cells. V. The isolation and growth of lymphoid cells infiltrating syngeneic solid tumors. J Immunol 1980; 125: 238-45.

Catalona WJ, Mann R, Nime F, Potvin C, Harty J , Gomolka D, et al. Identification of complement-receptor lymphocytes (B cells) in lymph nodes and tumor infiltrates. J Urol 1975; 114: 915-21.

Moore K, Moore M. Systemic and in-situ natural killer activity in tumour-bearing rats. Br J Cancer 1979; 39: 636-47. http://dx.doi.org/10.1038/bjc.1979.115

Vose BM. Functional activity of human tumor-infiltrating macrophages. Adv Exp Med Biol 1979; 114: 783-7. http://dx.doi.org/10.1007/978-1-4615-9101-6_128

Yoo SY, Kwon SM. Angiogenesis and its therapeutic opportunities. Mediators Inflamm 2013; 2013: 127170.

Folkman J, Merler E, Abernathy C, Williams G. Isolation of a tumor factor responsible for angiogenesis. J Exp Med 1971; 133: 275-88. http://dx.doi.org/10.1084/jem.133.2.275

Bernardo C, Costa C, Amaro T, Goncalves M, Lopes P, Freitas R, et al. Patient-derived Sialyl-Tn-positive Invasive Bladder Cancer Xenografts in Nude Mice: An Exploratory Model Study. Anticancer Res 2014; 34: 735-44.

Grisanzio C, Seeley A, Chang M, Collins M, Di Napoli A, Cheng SC, et al. Orthotopic xenografts of RCC retain histological, immunophenotypic and genetic features of tumours in patients. J Pathol 2011; 225: 212-21. http://dx.doi.org/10.1002/path.2929

Jager W, Moskalev I, Janssen C, Hayashi T, Awrey S, Gust KM, et al. Ultrasound-guided intramural inoculation of orthotopic bladder cancer xenografts: a novel high-precision approach. PLoS One 2013; 8: e59536. http://dx.doi.org/10.1371/journal.pone.0059536

Richmond A, Su Y. Mouse xenograft models vs GEM models for human cancer therapeutics. Dis Model Mech 2008; 1: 78-82. http://dx.doi.org/10.1242/dmm.000976

Huynh AS, Abrahams DF, Torres MS, Baldwin MK, Gillies RJ, Morse DL. Development of an orthotopic human pancreatic cancer xenograft model using ultrasound guided injection of cells. PLoS One 2011; 6: e20330. http://dx.doi.org/10.1371/journal.pone.0020330

Gu M, Roy S, Raina K, Agarwal C, Agarwal R. Inositol hexaphosphate suppresses growth and induces apoptosis in prostate carcinoma cells in culture and nude mouse xenograft: PI3K-Akt pathway as potential target. Cancer Res 2009; 69: 9465-72. http://dx.doi.org/10.1158/0008-5472.CAN-09-2805

Su X, Dong C, Zhang J, Su L, Wang X, Cui H, et al. Combination therapy of anti-cancer bioactive peptide with Cisplatin decreases chemotherapy dosing and toxicity to improve the quality of life in xenograft nude mice bearing human gastric cancer. Cell Biosci 2014; 4: 7. http://dx.doi.org/10.1186/2045-3701-4-7

Varna M, Lehmann-Che J, Turpin E, Marangoni E, El-Bouchtaoui M, Jeanne M, et al. p53 dependent cell-cycle arrest triggered by chemotherapy in xenografted breast tumors. Int J Cancer 2009; 124: 991-7. http://dx.doi.org/10.1002/ijc.24049

Pathak AK, Bhutani M, Saintigny P, Mao L. Heterotransplant mouse model cohorts of human malignancies: A novel platform for Systematic Preclinical Efficacy Evaluation of Drugs (SPEED). Am J Transl Res 2009; 1: 16-22.

Herter-Sprie GS, Kung AL and Wong KK. New cast for a new era: preclinical cancer drug development revisited. J Clin Invest 2013; 123: 3639-45. http://dx.doi.org/10.1172/JCI68340

Bousquet G, Feugeas JP, Ferreira I, Vercellino L, Jourdan N, Bertheau P, et al. Individual xenograft as a personalized therapeutic resort for women with metastatic triple-negative breast carcinoma. Breast Cancer Res 2014; 16: 401. http://dx.doi.org/10.1186/bcr3615

Fiebig HH, Maier A, Burger AM. Clonogenic assay with established human tumour xenografts: correlation of in vitro to in vivo activity as a basis for anticancer drug discovery. Eur J Cancer 2004; 40: 802-20. http://dx.doi.org/10.1016/j.ejca.2004.01.009

Hidalgo M, Bruckheimer E, Rajeshkumar NV, Garrido-Laguna I, De Oliveira E, Rubio-Viqueira B, et al. A pilot clinical study of treatment guided by personalized tumorgrafts in patients with advanced cancer. Mol Cancer Ther 2011; 10: 1311-6. http://dx.doi.org/10.1158/1535-7163.MCT-11-0233

Reyal F, Guyader C, Decraene C, Lucchesi C, Auger N, Assayag F, et al. Molecular profiling of patient-derived breast cancer xenografts. Breast Cancer Res 2012; 14: R11. http://dx.doi.org/10.1186/bcr3095

Mattie M, Christensen A, Chang MS, Yeh W, Said S, Shostak Y, et al. Molecular characterization of patient-derived human pancreatic tumor xenograft models for preclinical and translational development of cancer therapeutics. Neoplasia 2013; 15: 1138-50.

Chou J, Fitzgibbon MP, Mortales CL, Towlerton AM, Upton MP, Yeung R S, et al. Phenotypic and transcriptional fidelity of patient-derived colon cancer xenografts in immune-deficient mice. PLoS One 2013; 8: e79874. http://dx.doi.org/10.1002/ijc.11335

Cunha GR, Hayward SW, Wang YZ and Ricke WA. Role of the stromal microenvironment in carcinogenesis of the prostate. Int J Cancer 2003; 107: 1-10.

Cunha GR, Hayward SW, Wang YZ. Role of stroma in carcinogenesis of the prostate. Differentiation 2002; 70: 473-85. http://dx.doi.org/10.1046/j.1432-0436.2002.700902.x

Cespedes MV, Casanova I, Parreno M, Mangues R. Mouse models in oncogenesis and cancer therapy. Clin Transl Oncol 2006; 8: 318-29. http://dx.doi.org/10.1007/s12094-006-0177-7

Morton CL, Houghton PJ. Establishment of human tumor xenografts in immunodeficient mice. Nat Protoc 2007; 2: 247-50. http://dx.doi.org/10.1038/nprot.2007.25

Kim MP, Evans DB, Wang H, Abbruzzese JL, Fleming JB, Gallick GE. Generation of orthotopic and heterotopic human pancreatic cancer xenografts in immunodeficient mice. Nat Protoc 2009; 4: 1670-80. http://dx.doi.org/10.1038/nprot.2009.171

Bankert RB, Egilmez NK and Hess SD. Human-SCID mouse chimeric models for the evaluation of anti-cancer therapies. Trends Immunol 2001; 22: 386-93. http://dx.doi.org/10.1016/S1471-4906(01)01943-3

Mueller BM, Reisfeld RA. Potential of the scid mouse as a host for human tumors. Cancer Metastasis Rev 1991; 10: 193-200. http://dx.doi.org/10.1007/BF00050791

Xia Z, Taylor PR, Locklin RM, Gordon S, Cui Z, Triffitt JT. Innate immune response to human bone marrow fibroblastic cell implantation in CB17 scid/beige mice. J Cell Biochem 2006; 98: 966-80. http://dx.doi.org/10.1002/jcb.20730

Zhang X, Claerhout S, Prat A, Dobrolecki LE, Petrovic I, Lai Q, et al. A renewable tissue resource of phenotypically stable, biologically and ethnically diverse, patient-derived human breast cancer xenograft models. Cancer Res 2013; 73: 4885-97. http://dx.doi.org/10.1158/0008-5472.CAN-12-4081

Simpson-Abelson MR, Sonnenberg GF, Takita H, Yokota SJ, Conway TF, Jr., Kelleher RJ, Jr., et al. Long-term engraftment and expansion of tumor-derived memory T cells following the implantation of non-disrupted pieces of human lung tumor into NOD-scid IL2Rgamma(null) mice. J Immunol 2008; 180: 7009-18. http://dx.doi.org/10.4049/jimmunol.180.10.7009

Yano S, Nishioka Y, Izumi K, Tsuruo T, Tanaka T, Miyasaka M, et al. Novel metastasis model of human lung cancer in SCID mice depleted of NK cells. Int J Cancer 1996; 67: 211-7. http://dx.doi.org/10.1002/(SICI)1097-0215(19960717)67:2<211::AID-IJC11>3.0.CO;2-E

Bankert RB, Hess SD and Egilmez NK. SCID mouse models to study human cancer pathogenesis and approaches to therapy: potential, limitations, and future directions. Front Biosci 2002; 7: c44-62.

Peterson JK, Houghton PJ. Integrating pharmacology and in vivo cancer models in preclinical and clinical drug development. Eur J Cancer 2004; 40: 837-44. http://dx.doi.org/10.1016/j.ejca.2004.01.003

Loukopoulos P, Kanetaka K, Takamura M, Shibata T, Sakamoto M, Hirohashi S. Orthotopic transplantation models of pancreatic adenocarcinoma derived from cell lines and primary tumors and displaying varying metastatic activity. Pancreas 2004; 29: 193-203. http://dx.doi.org/10.1097/00006676-200410000-00004

Fidler IJ. New developments in in vivo models of neoplasia. Cancer Metastasis Rev 1991; 10: 191-2. http://dx.doi.org/10.1007/BF00050790

Shultz LD, Ishikawa F, Greiner DL. Humanized mice in translational biomedical research. Nat Rev Immunol 2007; 7: 118-30. http://dx.doi.org/10.1038/nri2017

Shultz LD, Brehm MA, Garcia-Martinez JV, Greiner DL. Humanized mice for immune system investigation: progress, promise and challenges. Nat Rev Immunol 2012; 12: 786-98. http://dx.doi.org/10.1038/nri3311

DeRose YS, Wang G, Lin YC, Bernard PS, Buys SS, Ebbert MT, et al. Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomes. Nat Med 2011; 17: 1514-20. http://dx.doi.org/10.1038/nm.2454

Proia DA, Kuperwasser C. Reconstruction of human mammary tissues in a mouse model. Nat Protoc 2006; 1: 206-14. http://dx.doi.org/10.1038/nprot.2006.31

Kojima M, Higuchi Y, Yokota M, Ishii G, Saito N, Aoyagi K, et al. Human subperitoneal fibroblast and cancer cell interaction creates microenvironment that enhances tumor progression and metastasis. PLoS One 2014; 9: e88018. http://dx.doi.org/10.1371/journal.pone.0088018

Iyer V, Klebba I, McCready J, Arendt LM, Betancur-Boissel M, Wu MF, et al. Estrogen promotes ER-negative tumor growth and angiogenesis through mobilization of bone marrow-derived monocytes. Cancer Res 2012; 72: 2705-13. http://dx.doi.org/10.1158/0008-5472.CAN-11-3287

Kuperwasser C, Chavarria T, Wu M, Magrane G, Gray JW, Carey L, et al. Reconstruction of functionally normal and malignant human breast tissues in mice. Proc Natl Acad Sci U S A 2004; 101: 4966-71. http://dx.doi.org/10.1073/pnas.0401064101

Verschraegen CF, Hu W, Du Y, Mendoza J, Early J, Deavers M, et al. Establishment and characterization of cancer cell cultures and xenografts derived from primary or metastatic Mullerian cancers. Clin Cancer Res 2003; 9: 845-52.

Schmidt KF, Ziu M, Schmidt NO, Vaghasia P, Cargioli TG, Doshi S, et al. Volume reconstruction techniques improve the correlation between histological and in vivo tumor volume measurements in mouse models of human gliomas. J Neurooncol 2004; 68: 207-15. http://dx.doi.org/10.1023/B:NEON.0000033364.43142.bf

Verstijnen CP, Arends JW, Moerkerk P, Schutte B, van der Linden E, Kuypers-Engelen B, et al. Culturing and xenografting of primary colorectal carcinoma cells: comparison of in vitro, and in vivo model and primary tumor. Anticancer Res 1988; 8: 1193-200.

Whiteford CC, Bilke S, Greer BT, Chen Q, Braunschweig TA, Cenacchi N, et al. Credentialing preclinical pediatric xenograft models using gene expression and tissue microarray analysis. Cancer Res 2007; 67: 32-40. http://dx.doi.org/10.1158/0008-5472.CAN-06-0610

Dodbiba L, Teichman J, Fleet A, Thai H, Sun B, Panchal D, et al. Primary esophageal and gastro-esophageal junction cancer xenograft models: clinicopathological features and engraftment. Lab Invest 2013; 93: 397-407. http://dx.doi.org/10.1038/labinvest.2013.8

Marangoni E, Vincent-Salomon A, Auger N, Degeorges A, Assayag F, de Cremoux P, et al. A new model of patient tumor-derived breast cancer xenografts for preclinical assays. Clin Cancer Res 2007; 13: 3989-98. http://dx.doi.org/10.1158/1078-0432.CCR-07-0078

John T, Kohler D, Pintilie M, Yanagawa N, Pham NA, Li M, et al. The ability to form primary tumor xenografts is predictive of increased risk of disease recurrence in early-stage non-small cell lung cancer. Clin Cancer Res 2011; 17: 134-41. http://dx.doi.org/10.1158/1078-0432.CCR-10-2224

Press JZ, Kenyon JA, Xue H, Miller MA, De Luca A, Miller DM, et al. Xenografts of primary human gynecological tumors grown under the renal capsule of NOD/SCID mice show genetic stability during serial transplantation and respond to cytotoxic chemotherapy. Gynecol Oncol 2008; 110: 256-64. http://dx.doi.org/10.1016/j.ygyno.2008.03.011

Nemati F, Sastre-Garau X, Laurent C, Couturier J, Mariani P, Desjardins L, et al. Establishment and characterization of a panel of human uveal melanoma xenografts derived from primary and/or metastatic tumors. Clin Cancer Res 2010; 16: 2352-62. http://dx.doi.org/10.1158/1078-0432.CCR-09-3066

Varna M, Bousquet G, Ferreira I, Goulard M, El-Bouchtaoui M, Artus PM, et al. Stability of preclinical models of aggressive renal cell carcinomas. Int J Clin Exp Pathol 2014; 7: 2950-62.

Gray DR, Huss WJ, Yau JM, Durham LE, Werdin ES, Funkhouser WK, Jr., et al. Short-term human prostate primary xenografts: an in vivo model of human prostate cancer vasculature and angiogenesis. Cancer Res 2004; 64: 1712-21. http://dx.doi.org/10.1158/0008-5472.CAN-03-2700

Sanz L, Cuesta AM, Salas C, Corbacho C, Bellas C, Alvarez-Vallina L. Differential transplantability of human endothelial cells in colorectal cancer and renal cell carcinoma primary xenografts. Lab Invest 2009; 89: 91-7. http://dx.doi.org/10.1038/labinvest.2008.108

Merk J, Rolff J, Becker M, Leschber G, Fichtner I. Patient-derived xenografts of non-small-cell lung cancer: a pre-clinical model to evaluate adjuvant chemotherapy? Eur J Cardiothorac Surg 2009; 36: 454-9. http://dx.doi.org/10.1016/j.ejcts.2009.03.054

Hylander BL, Punt N, Tang H, Hillman J, Vaughan M, Bshara W, et al. Origin of the vasculature supporting growth of primary patient tumor xenografts. J Transl Med 2013; 11: 110. http://dx.doi.org/10.1186/1479-5876-11-110

Montecinos VP, Godoy A, Hinklin J, Vethanayagam RR, Smith GJ. Primary xenografts of human prostate tissue as a model to study angiogenesis induced by reactive stroma. PLoS One 2012; 7: e29623. http://dx.doi.org/10.1371/journal.pone.0029623

Chang YS, di Tomaso E, McDonald DM, Jones R, Jain RK, Munn LL. Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood. Proc Natl Acad Sci U S A 2000; 97: 14608-13. http://dx.doi.org/10.1073/pnas.97.26.14608

Mihic-Probst D, Ikenberg K, Tinguely M, Schraml P, Behnke S, Seifert B, et al. Tumor cell plasticity and angiogenesis in human melanomas. PLoS One 2012; 7: e33571.

Bousquet G, Varna M, Ferreira I, Wang L, Mongiat-Artus P, Leboeuf C, et al. Differential regulation of sunitinib targets predicts its tumor-type-specific effect on endothelial and/or tumor cell apoptosis. Cancer Chemother Pharmacol 2013; 72: 1183-93. http://dx.doi.org/10.1007/s00280-013-2300-0

Dong Z, Imai A, Krishnamurthy S, Zhang Z, Zeitlin BD, Nor JE. Xenograft tumors vascularized with murine blood vessels may overestimate the effect of anti-tumor drugs: a pilot study. PLoS One 2013; 8: e84236.




How to Cite

Mariana Varna, Philippe Bertheau, & Luc G. Legrès. (2014). Tumor Microenvironment in Human Tumor Xenografted Mouse Models. Journal of Analytical Oncology, 3(3),  159–166. https://doi.org/10.6000/1927-7229.2014.03.03.6