Abstract 3926: Influence of tumor microenvironment on engraftment capacity of hematological cell lines in immunocompromized mice

Abstract

Abstract Hematological malignancies account for about 10% of newly diagnosed cancers in the US, their heterogeneity and diverse biological characteristics present unique therapeutic challenges. In order to develop more promising therapeutic strategies, the establishment of functional and reproducible in vivo models is widely pursued. A panel of 18 hematological cell lines comprising different entities including leukemia (acute lymphoblastic AML; chronic myeloid CML; chronic lymphatic leukemia CLL), diffuse large B cell lymphoma (DLBCL), as well as multiple myeloma (MM) was evaluated for in vivo engraftment using different mouse strains and application routes. 18 different cell lines were inoculated into 4 different immuncompromized mouse strains (NOG; NSG; NOD/SCID; SCID/beige nude) in 35 independent experiments. Cells were injected intravenously (i.v.), intratibialy (i.t.) or intraperitonealy (i.p.). Tumor growth was monitored via a) determination of overall survival, b) fluorescence-based in vivo imaging (IVI, Bruker FX, using CF750 labeled anti-hu CD33, CD19, CD45) c) flow cytometry and d) histological and IHC examination. Engraftment of hematological cell lines was clearly influenced by tumor entity, mouse strain and application route. The investigated AML cell lines engrafted in all three applied mouse strains (NOG; NSG; NOD/SCID) and injection routes. MOLM-13 infiltrated the bone marrow (BM) and the spleen (>90% infiltration, 21 days after tumor cell injection (=d21)), whereas MV4-11 cells disseminated mainly to the spleen (5% BM and 15% spleen infiltration, d21). In contrast THP-1 (80% BM and 2% spleen infiltration, d21) as well as NOMO-1 cells (30% BM and 3% spleen infiltration, d21) grew predominantly in the murine BM. MM cell lines (L363, RPMI8826, MM1R, MM1S) as well as B-CLL cell lines (Mec-1) failed to engraft reliably in NOD/SCID mice, irrespective of the application route. MM cells engrafted predominantly in the BM (20 - 60% depending on the cell line) of NSG mice when injected i.t.. i.v. injected MM cells did engraft in the BM but to a significantly lower extent than when injected i.t. (e.g. 20% vs. 2% BM infiltration of RPMI8226 cells, d35). Mec-1 cells infiltrated the BM and spleen of NSG and NOG mice reliably when injected i.v. and i.p. in the same individual (60% BM and 15% spleen infiltration, d28), whereas the same approach did not result in any engraftment when using SCID/beige nude mice. 3 out of 4 investigated DLBCL cell lines engrafted in vivo. Disseminated growth could be observed in NOG mice when injecting the cells i.v. or i.t. In all cases, tumors grew faster and infiltrated the BM more aggressively when injected I.t.. In summary, the engraftment of hematological cell lines strongly depends on the tumor microenvironment. The direct contact to the BM niche is a major survival benefit for the tumor cells as is the lack of NK cells in NOG and NSG mice. Citation Format: Eva Oswald, Kerstin Klingner, Ralph Waesch, Katja Zirlik, Monika Engelhardt, Julia B. Schüler. Influence of tumor microenvironment on engraftment capacity of hematological cell lines in immunocompromized mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3926. doi:10.1158/1538-7445.AM2014-3926