Browse > Article
http://dx.doi.org/10.14348/molcells.2016.2350

An Integrative Approach to Precision Cancer Medicine Using Patient-Derived Xenografts  

Cho, Sung-Yup (Department of Life Science, Ewha Womans University)
Kang, Wonyoung (Department of Life Science, Ewha Womans University)
Han, Jee Yun (Department of Life Science, Ewha Womans University)
Min, Seoyeon (Department of Life Science, Ewha Womans University)
Kang, Jinjoo (Department of Life Science, Ewha Womans University)
Lee, Ahra (Department of Life Science, Ewha Womans University)
Kwon, Jee Young (Department of Life Science, Ewha Womans University)
Lee, Charles (Department of Life Science, Ewha Womans University)
Park, Hansoo (Department of Life Science, Ewha Womans University)
Abstract
Cancer is a heterogeneous disease caused by diverse genomic alterations in oncogenes and tumor suppressor genes. Despite recent advances in high-throughput sequencing technologies and development of targeted therapies, novel cancer drug development is limited due to the high attrition rate from clinical studies. Patient-derived xenografts (PDX), which are established by the transfer of patient tumors into immunodeficient mice, serve as a platform for co-clinical trials by enabling the integration of clinical data, genomic profiles, and drug responsiveness data to determine precisely targeted therapies. PDX models retain many of the key characteristics of patients' tumors including histology, genomic signature, cellular heterogeneity, and drug responsiveness. These models can also be applied to the development of biomarkers for drug responsiveness and personalized drug selection. This review summarizes our current knowledge of this field, including methodologic aspects, applications in drug development, challenges and limitations, and utilization for precision cancer medicine.
Keywords
cancer drug development; cancer genomics; patient-derived xenografts; precision medicine;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Pao, W., Miller, V., Zakowski, M., Doherty, J., Politi, K., Sarkaria, I., Singh, B., Heelan, R., Rusch, V., Fulton, L., et al. (2004). EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc. Natl. Acad. Sci. USA 101, 13306- 13311.   DOI
2 Park, H., Cho, S.Y., Kim, H., Na, D., Han, J.Y., Chae, J., Park, C., Park, O.K., Min, S, Kang, J., et al. (2015). Genomic alterations in BCL2L1 and DLC1 contribute to drug sensitivity in gastric cancer. Proc. Natl. Acad. Sci. USA 112, 12492-12497.   DOI
3 Quintas-Cardama, A., and Cortes, J. (2009). Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood 113, 1619- 1630.   DOI
4 Reyal, F., Guyader, C., Decraene, C., Lucchesi, C., Auger, N., Assayag, F., De Plater, L., Gentien, D., Poupon, M.F., Cottu, P., et al. (2012). Molecular profiling of patient-derived breast cancer xenografts. Breast Cancer Res. 14, R11.   DOI
5 Reyes, G., Villanueva, A., Garcia, C., Sancho, F.J., Piulats, J., Lluis, F., and Capella, G. (1996). Orthotopic xenografts of human pancreatic carcinomas acquire genetic aberrations during dissemination in nude mice. Cancer Res. 56, 5713-5719.
6 Rongvaux, A., Willinger, T., Martinek, J., Strowig, T., Gearty, S.V., Teichmann, L.L., Saito, Y., Marches, F., Halene, S., Palucka, A.K., et al. (2014). Development and function of human innate immune cells in a humanized mouse model. Nat. Biotechnol. 32, 364-U230.   DOI
7 Rosen, J.M., and Jordan, C.T. (2009). The increasing complexity of the cancer stem cell paradigm. Science 324, 1670-1673.   DOI
8 Rosfjord, E., Lucas, J., Li, G., and Gerber, H.P. (2014). Advances in patient-derived tumor xenografts: From target identification to predicting clinical response rates in oncology. Biochem. Pharmacol. 91, 135-143.   DOI
9 Von Hoff, D.D., Ramanathan, R.K., Borad, M.J., Laheru, D.A., Smith, L.S., Wood, T.E., Korn, R.L., Desai, N., Trieu, V., Iglesias, J.L., et al. (2011). Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J. Clin. Oncol. 29, 4548-4554.   DOI
10 Von Hoff, D.D., Ervin, T., Arena, F.P., Chiorean, E.G., Infante, J., Moore, M., Seay, T., Tjulandin, S.A., Ma, W.W., Saleh, M.N., et al. (2013). Increased survival in pancreatic cancer with nabpaclitaxel plus gemcitabine. N. Engl. J. Med. 369, 1691-1703.   DOI
11 Weinstein, J.N., Collisson, E.A., Mills, G.B., Shaw, K.R.M., Ozenberger, B.A., Ellrott, K., Shmulevich, I., Sander, C., and Stuart, J.M. (2013). The cancer genome atlas pan-cancer analysis project. Nat. Genet. 45, 1113-1120.   DOI
12 Wetterauer, C., Vlajnic, T., Schuler, J., Gsponer, J.R., Thalmann, G.N., Cecchini, M., Schneider, J., Zellweger, T., Pueschel, H., Bachmann, A., et al. (2015). Early development of human lymphomas in a prostate cancer xenograft program using triple knock-out immunocompromised mice. Prostate 75, 585-592.   DOI
13 Whittle, J.R., Lewis, M.T., Lindeman, G.J., and Visvader, J.E. (2015). Patient-derived xenograft models of breast cancer and their predictive power. Breast Cancer Res. 17, 17.   DOI
14 Williams, S.A., Anderson, W.C., Santaguida, M.T., and Dylla, S.J. (2013). Patient-derived xenografts, the cancer stem cell paradigm, and cancer pathobiology in the 21st century. Lab. Invest. 93, 970-982.   DOI
15 Zhang, X.M., Claerhout, S., Prat, A., Dobrolecki, L.E., Petrovic, I., Lai, Q., Landis, M.D., Wiechmann, L., Schiff, R., Giuliano, M., et al. (2013). A Renewable tissue resource of phenotypically stable, biologically and ethnically diverse, patient-derived human breast cancer xenograft models. Cancer Res. 73, 4885-4897.   DOI
16 Bertolini, G., Roz, L., Perego, P., Tortoreto, M., Fontanella, E., Gatti, L., Pratesi, G., Fabbri, A., Andriani, F., Tinelli, S., et al. (2009). Highly tumorigenic lung cancer CD133(+) cells display stem-like features and are spared by cisplatin treatment. Proc. Natl. Acad. Sci. USA 106, 16281-16286.   DOI
17 Agliano, A., Martin-Padura, I., Mancuso, P., Marighetti, P., Rabascio, C., Pruneri, G., Shultz, L.D., and Bertolini, F. (2008). Human acute leukemia cells injected in NOD/LtSz-scid/IL-$2R\gamma$ null mice generate a faster and more efficient disease compared to other NOD/scid-related strains. Int. J. Cancer 123, 2222-2227.   DOI
18 Aparicio, S., Hidalgo, M., and Kung, A.L. (2015). Examining the utility of patient-derived xenograft mouse models. Nat. Rev. Cancer 15, 311-316.   DOI
19 Aytes, A., Mollevi, D.G., Martinez-Iniesta, M., Nadal, M., Vidal, A., Morales, A., Salazar, R., Capella, G., and Villanueva, A. (2012). Stromal interaction molecule 2 (STIM2) is frequently overexpressed in colorectal tumors and confers a tumor cell growth suppressor phenotype. Mol. Carcinog. 51, 746-753.   DOI
20 Bell, D., Berchuck, A., Birrer, M., Chien, J., Cramer, D.W., Dao, F., Dhir, R., DiSaia, P., Gabra, H., Glenn, P., et al. (2011). Integrated genomic analyses of ovarian carcinoma. Nature 474, 609-615.   DOI
21 Bertotti, A., Migliardi, G., Galimi, F., Sassi, F., Torti, D., Isella, C., Cora, D., Di Nicolantonio, F., Buscarino, M., Petti, C., et al. (2011). A molecularly annotated platform of patient-derived xenografts ("xenopatients") identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov. 1, 508-523.   DOI
22 Chen, K., Ahmed, S., Adeyi, O., Dick, J.E., and Ghanekar, A. (2012). Human solid tumor xenografts in immunodeficient mice are vulnerable to lymphomagenesis associated with Epstein-Barr virus. PLoS One 7, e39294.   DOI
23 Choi, S.Y.C., Lin, D., Gout, P.W., Collins, C.C., Xu, Y., and Wang, Y.Z. (2014). Lessons from patient-derived xenografts for better in vitro modeling of human cancer. Adv. Drug Deliver. Rev. 79-80, 222-237.   DOI
24 Das Thakur, M., Salangsang, F., Landman, A.S., Sellers, W.R., Pryer, N.K., Levesque, M.P., Dummer, R., McMahon, M., and Stuart, D.D. (2013). Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature 494, 251-255.   DOI
25 DiMasi, J.A., Reichert, J.M., Feldman, L., and Malins, A. (2013). Clinical approval success rates for investigational cancer drugs. Clin. Pharmacol. Ther. 94, 329-335.   DOI
26 de Groot, J.F., Fuller, G., Kumar, A.J., Piao, Y., Eterovic, K., Ji, Y.J., and Conrad, C.A. (2010). Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neuro. Oncol. 12, 233-242.   DOI
27 Delitto, D., Pham, K., Vlada, A.C., Sarosi, G.A., Thomas, R.M., Behrns, K.E., Liu, C., Hughes, S.J., Wallet, S.M., and Trevino, J.G. (2015). Patient-derived xenograft models for pancreatic adenocarcinoma demonstrate retention of tumor morphology through incorporation of murine stromal elements. Am. J. Pathol. 185, 1297-1303.   DOI
28 DeRose, Y.S., Wang, G.Y., Lin, Y.C., Bernard, P.S., Buys, S.S., Ebbert, M.T.W., Factor, R., Matsen, C., Milash, B.A., Nelson, E., et al. (2011). Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomes. Nat. Med. 17, 1514-1520   DOI
29 Ding, L., Ellis, M.J., Li, S.Q., Larson, D.E., Chen, K., Wallis, J., Harris, C.C., McLellan, M.D., Fulton, R.S., Fulton, L.L., et al. (2010). Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 464, 999-1005.   DOI
30 Dong, X., Guan, J., English, J.C., Flint, J., Yee, J., Evans, K., Murray, N., Macaulay, C., Ng, R.T., Gout, P.W., et al. (2010). Patientderived first generation xenografts of non-small cell lung cancers: promising tools for predicting drug responses for personalized chemotherapy. Clin. Cancer Res. 16, 1442-1451.   DOI
31 Dowst, H., Pew, B., Watkins, C., McOwiti, A., Barney, J., Qu, S., Becnel, L. B. (2015). Acquire: an open-source comprehensive cancer biobanking system. Bioinformatics 31, 1655-1662.   DOI
32 Gao, D., and Chen, Y. (2015). Organoid development in cancer genome discovery. Curr. Opin. Genet. Dev. 30, 42-48.   DOI
33 Eirew, P., Steif, A., Khattra, J., Ha, G., Yap, D., Farahani, H., Gelmon, K., Chia, S., Mar, C., Wan, A., et al. (2015). Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution. Nature 518, 422-426.   DOI
34 Fernandez de Sanmamamed, M., Lopez Rodriguez, I., Schalper, K.A., Onate, C., Azpilikueta, A., Rodriguez-Ruiz, M.E., Morales- Kastresana, A., Labiano, S., Perez-Gracia, J.L., Martin-Algarra, S., et al. (2015). Nivolumab and urelumab enhance antitumor activity of human T lymphocytes engrafted in Rag2-/-IL2R$\gamma$null immunodeficient mice. Cancer Res. 75, 3466-3478.   DOI
35 Fichtner, I., Rolff, J., Soong, R., Hoffmann, J., Hammer, S., Sommer, A., Becker, M., and Merk, J. (2008). Establishment of patientderived non-small cell lung cancer xenografts as models for the identification of predictive biomarkers. Clin. Cancer Res. 14, 6456-6468.   DOI
36 Gao, H., Korn, J.M., Ferretti, S., Monahan, J.E., Wang, Y., Singh, M., Zhang, C., Schnell, C., Yang, G., Zhang, Y., et al. (2015). Highthroughput screening using patient-derived tumor xenografts to predict clinical trial drug response. Nat. Med. 21, 1318-1325.   DOI
37 Garraway, L.A., Verweij, J., and Ballman, K.V. (2013). Precision oncology: an overview. J. Clin. Oncol. 31, 1803-1805.   DOI
38 Garrido-Laguna, I., Uson, M., Rajeshkumar, N.V., Tan, A.C., de Oliveira, E., Karikari, C., Villaroel, M.C., Salomon, A., Taylor, G., Sharma, R., et al. (2011). Tumor engraftment in nude mice and enrichment in stroma-related gene pathways predict poor survival and resistance to gemcitabine in patients with pancreatic cancer. Clin. Cancer Res. 17, 5793-5800.   DOI
39 Hidalgo, M., Bruckheimer, E., Rajeshkumar, N.V., Garrido-Laguna, I., De Oliveira, E., Rubio-Viqueira, B., Strawn, S., Wick, M.J., Martell, J., and Sidransky, D. (2011). A pilot clinical study of treatment guided by personalized tumorgrafts in patients with advanced cancer. Mol. Cancer Ther. 10, 1311-1316.   DOI
40 Girotti, M.R., Lopes, F., Preece, N., Niculescu-Duvaz, D., Zambon, A., Davies, L., Whittaker, S., Saturno, G., Viros, A., Pedersen, M., et al. (2015). Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma. Cancer Cell 27, 85-96.   DOI
41 Hidalgo, M., Amant, F., Biankin, A.V., Budinska, E., Byrne, A.T., Caldas, C., Clarke, R.B., de Jong, S., Jonkers, J., Maelandsmo, G.M., et al. (2014). Patient-derived xenograft models: an emerging platform for translational cancer research. Cancer Discov. 4, 998-1013.   DOI
42 Hoffman, R.M. (2015). Patient-derived orthotopic xenografts: better mimic of metastasis than subcutaneous xenografts. Nat. Rev. Cancer 15, 451-452.   DOI
43 John, T., Yanagawa, N., Kohler, D., Craddock, K.J., Bandarchi- Chamkhaleh, B., Pintilie, M., Sykes, J., To, C., Li, M., Panchal, D., et al. (2012). Characterization of lymphomas developing in immunodeficient mice implanted with primary human non-small cell lung cancer. J. Thorac. Oncol. 7, 1101-1108.   DOI
44 Johnson, J.I., Decker, S., Zaharevitz, D., Rubinstein, L.V., Venditti, J., Schepartz, S., Kalyandrug, S., Christian, M., Arbuck, S., Hollingshead, M., et al. (2001). Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials. Br. J. Cancer 84, 1424-1431.   DOI
45 Keysar, S.B., Astling, D.P., Anderson, R.T., Vogler, B.W., Bowles, D.W., Morton, J.J., Paylor, J.J., Glogowska, M.J., Le, P.N., Eagles- Soukup, J.R., et al. (2013). A patient tumor transplant model of squamous cell cancer identifies PI3K inhibitors as candidate therapeutics in defined molecular bins. Mol. Oncol. 7, 776- 790.   DOI
46 Joo, K.M., Kim, J., Jin, J., Kim, M., Seol, H.J., Muradov, J., Yang, H., Choi, Y.L., Park, W.Y., Kong, D.S., et al. (2013). Patient-specific orthotopic glioblastoma xenograft models recapitulate the histopathology and biology of human glioblastomas in situ. Cell Rep. 3, 260-273.   DOI
47 Julien, S., Merino-Trigo, A., Lacroix, L., Pocard, M., Goere, D., Mariani, P., Landron, S., Bigot, L., Nemati, F., Dartigues, P., et al. (2012). Characterization of a large panel of patient-derived tumor xenografts representing the clinical heterogeneity of human colorectal cancer. Clin. Cancer Res. 18, 5314-5328.   DOI
48 Kimple, R.J., Harari, P.M., Torres, A.D., Yang, R.Z., Soriano, B.J., Yu, M., Armstrong, E.A., Blitzer, G.C., Smith, M.A., Lorenz, L.D., et al. (2013). Development and characterization of HPV-positive and HPV-negative head and neck squamous cell carcinoma tumorgrafts. Clin. Cancer Res. 19, 855-864.   DOI
49 Koboldt, D.C., Fulton, R.S., McLellan, M.D., Schmidt, H., Kalicki- Veizer, J., McMichael, J.F., Fulton, L.L., Dooling, D.J., Ding, L., Mardis, E.R., et al. (2012). Comprehensive molecular portraits of human breast tumours. Nature 490, 61-70.   DOI
50 Kopetz, S., Lemos, R., and Powis, G. (2012). The promise of patient- derived xenografts: the best laid plans of mice and men. Clin. Cancer Res. 18, 5160-5162.   DOI
51 Kung, A.L. (2007). Practices and pitfalls of mouse cancer models in drug discovery. Adv. Cancer Res. 96, 191-212.
52 Lin, D., Wyatt, A. W., Xue, H., Wang, Y., Dong, X., Haegert, A., Wu, R., Brahmbhatt, S., Mo, F., Jong, L., et al. (2014). High fidelity patient-derived xenografts for accelerating prostate cancer discovery and drug development. Cancer Res. 74, 1271-1283.   DOI
53 Lai, A., Tran, A., Nghiemphu, P.L., Pope, W.B., Solis, O.E., Selch, M., Filka, E., Yong, W.H., Mischel, P.S., Liau, L.M., et al. (2011). Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme. J. Clin. Oncol. 29, 142-148.   DOI
54 Landis, M.D., Lehmann, B.D., Pietenpol, J.A., and Chang, J.C. (2013). Patient-derived breast tumor xenografts facilitating personalized cancer therapy. Breast Cancer Res. 15, 201.   DOI
55 Li, S.Q., Shen, D., Shao, J.Y., Crowder, R., Liu, W.B., Prat, A., He, X.P., Liu, S.Y., Hoog, J., Lu, C., et al. (2013). Endocrine-therapyresistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts. Cell Rep. 4, 1116-1130.   DOI
56 Macconaill, L.E., and Garraway, L.A. (2010). Clinical implications of the cancer genome. J. Clin. Oncol. 28, 5219-5228.   DOI
57 Marangoni, E., Vincent-Salomon, A., Auger, N., Degeorges, A., Assayag, F., de Cremoux, P., de Plater, L., Guyader, C., De Pinieux, G., Judde, J.G., et al. (2007). A new model of patient tumorderived breast cancer xenografts for preclinical assays. Clin. Cancer Res. 13, 3989-3998.   DOI
58 Masso-Valles, D., Jauset, T., Serrano, E., Sodir, N.M., Pedersen, K., Affara, N.I., Whitfield, J.R., Beaulieu, M.E., Evan, G.I., Elias, L., et al. (2015). Ibrutinib exerts potent antifibrotic and antitumor activities in mouse models of pancreatic adenocarcinoma. Cancer Res. 75, 1675-1681.   DOI
59 Morton, C.L., and Houghton, P.J. (2007). Establishment of human tumor xenografts in immunodeficient mice. Nat. Protoc. 2, 247- 250.   DOI
60 Mattie, M., Christensen, A., Chang, M.S., Yeh, W., Said, S., Shostak, Y., Capo, L., Verlinsky, A., An, Z.L., Joseph, I., et al. (2013). Molecular characterization of patient-derived human pancreatic tumor xenograft models for preclinical and translational development of cancer therapeutics. Neoplasia 15, 1124-1136.
61 Morton, J.J., Bird, G., Keysar, S.B., Astling, D.P., Lyons, T.R., Anderson, R.T., Glogowska, M.J., Estes, P., Eagles, J.R., Le, P.N., et al. (2015). XactMice: humanizing mouse bone marrow enables microenvironment reconstitution in a patient-derived xenograft model of head and neck cancer. Oncogene (Epub ahead of print).
62 Muzny, D.M., Bainbridge, M.N., Chang, K., Dinh, H.H., Drummond, J.A., Fowler, G., Kovar, C.L., Lewis, L.R., Morgan, M.B., Newsham, I.F., et al. (2012). Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330-337.   DOI
63 Nardella, C., Lunardi, A., Patnaik, A., Cantley, L.C., and Pandolfi, P.P. (2011). The APL paradigm and the "co-clinical trial" project. Cancer Discov. 1, 108-116.   DOI
64 Nemati, F., Sastre-Garau, X., Laurent, C., Couturier, J., Mariani, P., Desjardins, L., Piperno-Neumann, S., Lantz, O., Asselain, B., Plancher, C., et al. (2010). Establishment and characterization of a panel of human uveal melanoma xenografts derived from primary and/or metastatic tumors. Clin. Cancer Res. 16, 2352- 2362.   DOI
65 Ostman, A. (2012). The tumor microenvironment controls drug sensitivity. Nat. Med. 18, 1332-1334.   DOI
66 Siolas, D., and Hannon, G.J. (2013). Patient-derived tumor xenografts: transforming clinical samples into mouse models. Cancer Res. 73, 5315-5319.   DOI
67 Schatton, T., Murphy, G.F., Frank, N.Y., Yamaura, K., Waaga- Gasser, A.M., Gasser, M., Zhan, Q., Jordan, S., Duncan, L.M., Weishaupt, C., et al. (2008). Identification of cells initiating human melanomas. Nature 451, 345-349.   DOI
68 Scott, C.L., Becker, M.A., Haluska, P., and Samimi, G. (2013). Patient- derived xenograft models to improve targeted therapy in epithelial ovarian cancer treatment. Front. Oncol. 3, 295.
69 Shaw, A.T., Yeap, B.Y., Solomon, B.J., Riely, G.J., Gainor, J., Engelman, J.A., Shapiro, G.I., Costa, D.B., Ou, S.H.I., Butaney, M., et al. (2011). Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol. 12, 1004-1012.   DOI
70 Slamon, D., Eiermann, W., Robert, N., Pienkowski, T., Martin, M., Press, M., Mackey, J., Glaspy, J., Chan, A., Pawlicki, M., et al. (2011). Adjuvant trastuzumab in HER2-positive breast cancer. N. Engl. J. Med. 365, 1273-1283.   DOI
71 Tentler, J.J., Tan, A.C., Weekes, C.D., Jimeno, A., Leong, S., Pitts, T.M., Arcaroli, J.J., Messersmith, W.A., and Eckhardt, S.G. (2012). Patient-derived tumour xenografts as models for oncology drug development. Nat. Rev. Clin. Oncol. 9, 338-350.   DOI
72 Verhaak, R.G.W., Hoadley, K.A., Purdom, E., Wang, V., Qi, Y., Wilkerson, M.D., Miller, C.R., Ding, L., Golub, T., Mesirov, J.P., et al. (2010). Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17, 98-110.   DOI
73 Zhao, X.M., Liu, Z.G., Yu, L.T., Zhang, Y.J., Baxter, P., Voicu, H., Gurusiddappa, S., Luan, J., Su, J.M., Leung, H.C.E., et al. (2012). Global gene expression profiling confirms the molecular fidelity of primary tumor-based orthotopic xenograft mouse models of medulloblastoma. Neuro. Oncol. 14, 574-583.   DOI
74 Zhang, L.H., Liu, Y.Q., Wang, X.H., Tang, Z.Y., Li, S.X., Hu, Y., Zong, X.L., Wu, X.J., Bu, Z.D., Wu, A.W., et al. (2015). The extent of in flammatory infiltration in primary cancer tissues is associated with lymphomagenesis in immunodeficient mice. Sci. Rep. 5, 9447.   DOI