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Inhibition of the Kit ligand/c-Kit axis attenuates metastasis in a mouse model mimicking local breast cancer relapse after radiotherapy.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2012 Aug 15; Vol. 18 (16), pp. 4365-74. Date of Electronic Publication: 2012 Jun 18. - Publication Year :
- 2012
-
Abstract
- Purpose: Local breast cancer relapse after breast-saving surgery and radiotherapy is associated with increased risk of distant metastasis formation. The mechanisms involved remain largely elusive. We used the well-characterized 4T1 syngeneic, orthotopic breast cancer model to identify novel mechanisms of postradiation metastasis.<br />Experimental Design: 4T1 cells were injected in 20 Gy preirradiated mammary tissue to mimic postradiation relapses, or in nonirradiated mammary tissue, as control, of immunocompetent BALB/c mice. Molecular, biochemical, cellular, histologic analyses, adoptive cell transfer, genetic, and pharmacologic interventions were carried out.<br />Results: Tumors growing in preirradiated mammary tissue had reduced angiogenesis and were more hypoxic, invasive, and metastatic to lung and lymph nodes compared with control tumors. Increased metastasis involved the mobilization of CD11b(+)c-Kit(+)Ly6G(high)Ly6C(low)(Gr1(+)) myeloid cells through the HIF1-dependent expression of Kit ligand (KitL) by hypoxic tumor cells. KitL-mobilized myeloid cells homed to primary tumors and premetastatic lungs, to give rise to CD11b(+)c-Kit(-) cells. Pharmacologic inhibition of HIF1, silencing of KitL expression in tumor cells, and inhibition of c-Kit with an anti-c-Kit-blocking antibody or with a tyrosine kinase inhibitor prevented the mobilization of CD11b(+)c-Kit(+) cells and attenuated metastasis. C-Kit inhibition was also effective in reducing mobilization of CD11b(+)c-Kit(+) cells and inhibiting lung metastasis after irradiation of established tumors.<br />Conclusions: Our work defines KitL/c-Kit as a previously unidentified axis critically involved in promoting metastasis of 4T1 tumors growing in preirradiated mammary tissue. Pharmacologic inhibition of this axis represents a potential therapeutic strategy to prevent metastasis in breast cancer patients with local relapses after radiotherapy.
- Subjects :
- Animals
Antineoplastic Agents administration & dosage
CD11b Antigen metabolism
Cell Line, Tumor
Disease Models, Animal
Female
Humans
Hypoxia
Hypoxia-Inducible Factor 1 metabolism
Lung Neoplasms metabolism
Lung Neoplasms secondary
Mammary Neoplasms, Experimental drug therapy
Mammary Neoplasms, Experimental radiotherapy
Mice
Mice, Inbred C57BL
Neoplasm Metastasis
Neoplasm Recurrence, Local
Neovascularization, Pathologic drug therapy
Tumor Burden
Antineoplastic Agents pharmacology
Mammary Neoplasms, Experimental metabolism
Mammary Neoplasms, Experimental pathology
Proto-Oncogene Proteins c-kit metabolism
Signal Transduction drug effects
Stem Cell Factor metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 18
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 22711708
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-11-3028