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Intravital Microscopy of Monocyte Homing and Tumor-Related Angiogenesis in a Murine Model of Peripheral Arterial Disease
Published on: August 26, 2017
Host acid sphingomyelinase regulates microvascular function not tumor immunity
Monica Garcia-Barros1, Daniel Lacorazza, Howard Petrie
1Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Abstract:
Previous studies provided evidence that MCA/129 fibrosarcomas and B16 melanomas grow 2- to 4-fold faster in acid sphingomyelinase (asmase)-deficient mice than in asmase(+/+) littermates and are resistant to single-dose irradiation due to inability to mount an apoptotic response in tumor microvascular endothelium. However, others postulated the differences might be associated with a host antitumor immune response in asmase(+/+) mice that is not expressed in asmase(-/-) mice due to phenotypic deficiency in antitumor immunity. The present studies demonstrate that none of the tumor-host combinations displayed the classic criteria of an immunogenic tumor because they lacked endotumoral or peritumoral infiltrates almost entirely. Furthermore, neither MCA/129 fibrosarcoma nor B16 melanoma tumors showed differences in growth or radioresponsiveness when implanted into mutant mouse models (Rag(-/-) and MEF(-/-)) lacking functional immune cell [natural killer (NK), NK-T, T, and B cells] populations. Additionally, development and function of B-, T-, and NK-cell populations in asmase(-/-) mice were normal, indistinguishable from their wild-type littermates. These data provide definitive evidence that MCA/129 fibrosarcomas and B16F1 melanomas do not elicit a host immune response in wild-type mice and that the asmase(-/-) phenotype is not deficient in antitumor immunity, supporting the notion that the patterns of tumors growth and radiation response are conditionally linked to the ability of the tumor endothelium to undergo ASMase-mediated apoptosis.
Insights
Tumor growth and radiation resistance in acid sphingomyelinase (asmase)-deficient mice are not due to immune response differences. These patterns are linked to the tumor endothelium's ability to undergo ASMase-mediated apoptosis.
Area of Science:
- Oncology
- Immunology
- Biochemistry
Background:
- Previous studies suggested acid sphingomyelinase (asmase) deficiency impacts tumor growth and radiation response.
- Hypotheses included differences in host antitumor immunity or tumor microvascular endothelium apoptosis.
Purpose of the Study:
- To investigate whether immune responses or tumor endothelial cell apoptosis mediate observed differences in tumor growth and radioresponsiveness in asmase-deficient mice.
- To definitively link tumor growth and radiation response patterns to specific mechanisms.
Main Methods:
- Tumor implantation (MCA/129 fibrosarcoma, B16 melanoma) into asmase-deficient and wild-type mice.
- Assessment of tumor immunogenicity via infiltrates.
- Tumor growth and radioresponsiveness evaluation in immune-deficient mouse models (Rag-/-, MEF(-/-)).
- Analysis of immune cell populations (B, T, NK) in asmase-deficient mice.
Main Results:
- Tumor-host combinations lacked criteria for immunogenic tumors, showing minimal infiltrates.
- No significant differences in tumor growth or radioresponsiveness were observed in immune-deficient mouse models.
- Immune cell populations in asmase-deficient mice were normal and comparable to wild-type littermates.
- MCA/129 fibrosarcomas and B16F1 melanomas did not elicit a host immune response in wild-type mice.
Conclusions:
- The observed differences in tumor growth and radiation response are not attributable to a deficient host antitumor immune response in asmase-deficient mice.
- The asmase(-/-) phenotype does not exhibit a deficiency in antitumor immunity.
- Tumor growth and radiation response are conditionally linked to the tumor endothelium's capacity for acid sphingomyelinase-mediated apoptosis.
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