Establishment of a new in vivo model for human T-cell lymphoblastic leukemia (T-ALL) suitable for evaluation of the tumor stromal component

AMOROS, M.; CARYOL, F.; DÍ­AZ FLAQUE, M.C.; GUTIÉRREZ, L.; PODHAJCER, O.; CERCHIETTI, L. ; CREMASCHI, G.; BOLONTRADE, M.F.

San Diego

Simposio; 105th Annual Meeting, American Association for Cancer Research (AACR); 2014

AACR

T-cell lymphoblastic leukemia (T-ALL) is a hematological hematopoietic T cell precursor disorder with a not well defined etiology, although it would be linked to NOTCH signaling defects. CUTLL1 (Columbia University T-cell Lymphoblastic Lymphoma 1) is a human T-ALL cell line displaying biological responses to NOTCH inhibition, thus mimicking the disease�s etiology. The absence of human T-ALL cell lines with verifiably clinical aspects turns the establishment of an in vivo model an asset for preclinical assays; further, it serves to study the interaction between disease-mimicking cells and their surrounding niche. We have established an in vivo model for T-ALL in immunosuppressed NOD.CB17-Prkdc<scid>/J mice using CUTLL1 cells. Tumors developed after subcutaneous inoculation of a minimum dose of 2x10E7 cells and became visible 2.5 weeks post-inoculation into the right flank (809.1�67.33 mmE3). Administration of larger cell doses (4x10E7) did not affect the lapse at which tumors appear, but originated larger tumors (3830�1571 mmE3, p<0.05). Tumors were histological characterized indicating high neoplastic proliferation infiltrating the tumor stroma with high content of fibroblast-like cells and microvessels.   Tumor progression is modulated by microenvironmental factors, among them stromal cells regulating neoplastic cells. Since Mesenchymal stromal cells (MSCs) are incorporated into the tumor microenvironment, we evaluated the participation of MSCs as stromal component in this model. We administered MSCs into lymphoma-bearing mice and measured MSCs tumor stroma homing. MSCs tumor homing ability of pre-labeled DiR/CMDiI+ MSCs injected intravenously (1x10E6 cells) was measured by infrared detection and microscopic examination.  MSCs levels at the tumor stroma reached highest values at smallest tumor volume (3,967x10E5 p/sec/cm2/sr /1004,372mm3) indicating a negative correlation between tumor size and MSCs homing ability and pointing at the high homing MSCs capacity into a niche of hematological neoplastic cells. Microenvironmental tumor factors may directly affect cell migration and promote tumor progression. We evaluated MSCs migratory in vitro capacity observing that MSCs are able to respond to chemotactic stimuli derived from CUTLL1 cells. This is the first report to our knowledge, of a xenomodel using the clinically representative cell line CUTLL1. The establishment of an in vivo model with T-ALL clinical aspects such as Notch signaling defects, serves as a relevant model and allows the study of stromal and neoplastic cell interaction within an in vivo tumor microenvironment.