Inhibition of the Kit ligand/c-Kit axis attenuates metastasis in a mouse model mimicking local breast cancer relapse after radiotherapy.
OBJECTIVE
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.


METHODS
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.


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.


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.
Department of Radio-Oncology, Centre Hospitalier Universitaire Vaudois, Switzerland.
François
F
Kuonen
Julien
J
Laurent
Chiara
C
Secondini
Girieca
G
Lorusso
Jean-Christophe
JC
Stehle
Thierry
T
Rausch
Eveline
E
Faes-Van't Hull
Grégory
G
Bieler
Gian-Carlo
GC
Alghisi
Reto
R
Schwendener
Snezana
S
Andrejevic-Blant
René-Olivier
RO
Mirimanoff
Curzio
C
Rüegg
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D039481:CD11b Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D000860:Hypoxia; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology* / Q000532:radiotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D019089:Stem Cell Factor / Q000378:metabolism*; D047368:Tumor Burden
D000970:Antineoplastic Agents; D039481:CD11b Antigen; D051793:Hypoxia-Inducible Factor 1; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit