Blockade of Notch Signaling in Tumor-Bearing Mice May Lead to Tumor Regression, Progression, or Metastasis, Depending on Tumor Cell Types

Mice, Knockout 0301 basic medicine 0303 health sciences Neovascularization, Pathologic Receptors, Notch Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Neoplasms. Tumors. Oncology. Including cancer and carcinogens Neoplasms, Experimental 3. Good health Mice 03 medical and health sciences Neutrophil Infiltration Neoplasm Regression, Spontaneous Cell Line, Tumor Immunoglobulin J Recombination Signal Sequence-Binding Protein Disease Progression Tumor Cells, Cultured Animals Humans Neoplasm Metastasis RC254-282 Cell Proliferation Signal Transduction
DOI: 10.1593/neo.81008 Publication Date: 2015-04-23T13:02:33Z
ABSTRACT
It has been reported that blocking Notch signaling in tumor-bearing mice results in abortive angiogenesis and tumor regression. However, given that Notch signaling influences numerous cellular processes in vivo, a comprehensive evaluation of the effect of Notch inactivation on tumor growth would be favorable. In this study, we inoculated four cancer cell lines in mice with the conditional inactivation of recombination signal-binding protein-Jkappa (RBP-J), which mediates signaling from all four mammalian Notch receptors. We found that whereas three tumors including hepatocarcinoma, lung cancer, and osteogenic sarcoma grew slower in the RBP-J-deficient mice, at least a melanoma, B16, grew significantly faster in the RBP-J-deficient mice than in the controls, suggesting that the RBP-J-deficient hosts could provide permissive cues for tumor growth. All these tumors showed increased microvessels and up-regulated hypoxia-inducible factor 1alpha, suggesting that whereas defective angiogenesis resulted in hypoxia, different tumors might grow differentially in the RBP-J-deleted mice. Similarly, increased infiltration of Gr1(+)/Mac1(+) cells were noticed in tumors grown in the RBP-J-inactivated mice. Moreover, we found that when inoculated in the RBP-J knockout hosts, the H22 hepatoma cells had a high frequency of metastasis and lethality, suggesting that at least for H22, deficiency of environmental Notch signaling favored tumor metastasis. Our findings suggested that the general blockade of Notch signaling in tumor-bearing mice could lead to defective angiogenesis in tumors, but depending on tumor cell types, general inhibition of Notch signaling might result in tumor regression, progression, or metastasis.
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