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
AUTHORS (10)
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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