Blockade of Notch signaling in tumor-bearing mice may lead to tumor regression, progression, or metastasis, depending on tumor cell types.
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.
Hu
Xing-Bin
XB
State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Feng
Fan
F
Wang
Yao-Chun
YC
Wang
Lin
L
He
Fei
F
Dou
Guo-Rui
GR
Liang
Liang
L
Zhang
Hong-Wei
HW
Liang
Ying-Min
YM
Han
Hua
H
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009365:Neoplasm Regression, Spontaneous / Q000235:genetics; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D020556:Neutrophil Infiltration / Q000235:genetics; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D014407:Tumor Cells, Cultured
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497571:Rbpj protein, mouse; D051880:Receptors, Notch