Increased primary tumor growth in mice null for β3- or β3/β5-integrins or selectins

Abstract

Expression of ␣v␤3-or ␣v␤5-integrins and selectins is widespread on blood cells and endothelial cells. Here we report that human tumor cells injected s.c. into mice lacking ␤3-or ␤3͞␤5-integrins or various selectins show enhanced tumor growth compared with growth in control mice. There was increased angiogenesis in mice lacking ␤3-integrins, but no difference in structure of the vessels was observed by histology or by staining for NG2 and smooth muscle actin in pericytes. Bone marrow transplants suggest that the absence of ␤3-integrins on bone marrow-derived host cells contributes to the enhanced tumor growth in ␤3-null mice, although few, if any, bone marrow-derived endothelial cells were found in the tumor vasculature. Tumor growth also was affected by bone marrow-derived cells in mice lacking any one or all three selectins, implicating both leukocyte and endothelial selectins in tumor suppression. Reduced infiltration of macrophages was observed in tumors grown in mice lacking either ␤3-integrins or selectins. These results implicate cells of the innate immune system, macrophages or perhaps natural killer cells, in each case dependent on integrins and selectins, in tumor suppression.tumors ͉ bone marrow transplants ͉ cell adhesion ͉ innate immunity W e have previously investigated the growth and metastasis of transplanted tumors in mice lacking specific celladhesion receptors, namely integrins (1-3) or selectins (4-6).In mice lacking ␣v-integrins (␣v␤3 and ␣v␤5), tumors grow larger; this growth is accompanied by enhanced tumor angiogenesis (2). However, it is unclear whether other factors, such as altered vessel morphology, pericyte recruitment, or altered immune responses in the integrin-deficient mice, may contribute to the enhanced tumor growth.In the case of selectins, we have shown that experimental metastases to the lungs are reduced in mice lacking P-and͞or L-selectins (4-6). This reduction is believed to result from the tumor cells' expression of ligands for selectins such that selectins on host platelets, leukocytes, or endothelial cells can bind these ligands and promote metastatic arrest in the lungs after tail vein injection (7-10). Examination of this hypothesis using a more complete model of metastasis, such as metastasis from a s.c. site, would be desirable.Given these two prior lines of investigation and the questions they raised, we have investigated further the s.c. growth of xenotransplanted tumors in mice lacking various combinations of integrins or selectins. We report here results indicating that both ␤3-integrins and selectins contribute to host responses suppressing tumor growth. In each case, bone marrow (BM)-derived host cells, dependent on integrins or selectins, seem to inhibit tumor growth, and in the absence of these adhesion receptors tumors grow significantly larger. Materials and MethodsMice. All mice were generated in our own laboratory. ␤3-Integrinnull mice (2, 11-12) were intercrossed with mice lacking the Rag2 gene (13) and with mice lacking ␤5-integrin (14) to generate mi...

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