Abstract 404: Murine lymphomas selected by growth rate: Aggressiveness, galectin-1 (Gal-1) expression and response to low doses of cyclophosphamide (Cy)

Abstract

L-DGE is a spontaneous poorly differentiated murine lymphoma. During tumor growth it develops lymph node metastasis at a low frequency. Gal-1 is an immunomodulatory protein that acts as a regulator of T cell homeostasis and plays an important role in immune tolerance and tumor-immune escape. Overexpression of Gal-1 is associated with tumor progression and metastasis. Based on our previous findings, our aim was to obtain by a divergent selection two L-DGE variants that differ in tumor growth rate in order to study Gal-1 expression as well as their response to Cy. Two selection experiments were carried out. 1) L-DGE was s.c. implanted on 12 BALB/c mice (day 0). On day 14 the tumor displaying the largest volume was chosen as donor for the next passage to 4 mice. This higher-volume-selection was repeated for 25 serial passages, every 14 days and the tumor thus obtained was named L-DGE/M. 2) L-DGE was s.c. implanted on 12 BALB/c mice (day 0). On day 21, the tumor with the lowest growth rate was chosen as a donor and implanted into 6 mice and repeated through 16 serial passages. As a result of this selection L-DGE/L was obtained. We challenged mice (n=20/group) with L-DGE, L-DGE/M and L-DGE/L and studied tumor growth, metastatic capacity, galectin-1 expression and response to a single low dose Cy (25 mg/kg). Tumor volume vs. Time data was adjusted with an exponential curve and the growth rate was calculated. Gal-1 expression was studied by Western Blot in tumor and metastases homogenates. L-DGE/M growth rate was higher than that of L-DGE (p<0.01). L-DGE/L grew slower than L-DGE but did not differ statistically. The % of metastasis displayed by L-DGE/M was higher than that displayed by L-DGE (p=0.009) whereas L-DGE/L did not differ from L-DGE. Median survival times were 15, 20 and 26 days for L-DGE/M, L-DGE and L-DGE/L, respectively (p<0.0001). Tumor regressions were also different: 5%, 20% and 30%, respectively. Interestingly, Gal-1 expression in L-DGE/M primary tumors was higher (p=0.042) and in L-DGE/L lower (p=0.013) than in L-DGE, whereas in lymph-node metastases from L-DGE/M and L-DGE was 20% lower than their respective primary tumors, a pattern that we had already found in a rat lymphoma model. Finally, Cy treatment had different impact on tumor progression on these variants. While it increased median survival times of L-DGE, L-DGE/L and L-DGE/M-bearing mice, it induced exponential tumor volume decay with different rates on L-DGE, L-DGE/L and L-DGE/M (p=0.0001). Two lymphoma variants were obtained, of which, the more aggressive overexpresses Gal-1 in primary tumor while the slowly growing variant underexpresses this immunomodulatory protein. These differences also correlate with different responses to immunomodulatory doses of Cy. These results show a strong relationship between galectin-1 expression and tumor aggressiveness, a fact that could be of great value for prognosis and therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 404.