The International Complex Trait Consortium

Recombinant Inbred Mice Represent a Novel T-cell Mediated Immune Response Tumor Model

John D. Mountz 1,3, William E. Grizzle2, Ping-Ar Yang1, Xin Xu1, Sheher Sun1, Gary E.Van Zant4, Robert W. Williams5, Hui-Chen Hsu1, Huang-Ge Zhang1,3

1The University of Alabama at Birmingham, Department of Medicine, Division of Clinical Immunology and Rheumatology, Birmingham, Alabama 35294 USA
2The Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294
3Veterans Administration Medical Center, 700 South 19th Street, Birmingham, Alabama 35233
4The Markey Cancer Center, Division of Hematology/Oncology, The University of Kentucky Medical Center, Lexington, KY 40536
5Center for Neuroscience and Department of Anatomy and Neurobiology, University of Tennessee, Memphis, TN 38163

ABSTRACT
 
To develop a better animal model for studying the effects of the host environment in neoplasia, we injected various genetically well-characterized H-2d recombinant inbred (RI) strains of BXD mice with syngeneic breast cancer cells (TS/A), and monitored the cytotoxic T cell response and the growth of the tumor over time. The T cell immune response eliminated tumor development in mice that underwent tumor regression since T-cell depletion in tumor susceptible strains of BXD RI mice resulted in aggressive tumor growth. There was a correlation between tumor regression and cytotoxic T cell response to the TS/A tumor cells. There was a dramatic difference in the growth of the implanted breast cancer cells among the 14 BXD RI strains with four patterns of tumor development being observed: Type I: The implanted tumor cells grew rapidly in the first two weeks, necrosis of the tumors was observed, and metastases to the intestinal lymph nodes and pancreas occurred; Type II: The implanted tumor cells grew slowly and attained a size after day 50 that required sacrifice of the animal, with tumor necrosis being rare and metastases absent; Type III: The implanted tumor cells grew initially but underwent a slow decline after 4 weeks; and Type IV: The implanted tumor cells failed to develop. Apoptosis of the implanted tumor cells was responsible for the regression of tumor nodules. The tumor size was regulated by a QTL that mapped to proximal Chromosome 16 in mouse.



Fig. 1. The ability of TS/A cells to form tumors differs among the BXD RI strains of mice. Syngeneic murine breast cancer cells TS/A were injected subcutaneously into 14 BXD RI strains and the parental strains, DBA/2 and B6 (H-2d) mice (1.2 × 105 cells/flank at three sites in 50 µl of PBS for each site, 5 mice per BXD RI strain). Tumor volumes were measured every five days. Each point represents the mean volume ± S.D. of the three tumors of the five mice from each group. The strains of BXD RI mice were categorized as supporting type 1 (A), type 2 (B), type 3 (C), or type 4 (D) tumor characteristics as described in the text.