Search

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 post-radiation metastasis. Experimental Design: 4T1 cells were injected in 20 Gy pre-irradiated mammary tissue, to mimic post-radiation relapses, or in non-irradiated mammary tissue, as control, of immunocompetent BALB/c mice. Molecular, biochemical, cellular, histological analyses, adoptive cell transfer, genetic and pharmacological interventions were performed. Results: Tumors growing in pre-irradiated mammary tissue had reduced angiogenesis, were more hypoxic, invasive and metastatic to lung and lymph nodes compared to control tumors. Increased metastasis involved the mobilization of CD11b+c-Kit+Ly6GhighLy6Clow(Gr1+) myeloid cells through the HIF1-dependent expression of KitL by hypoxic tumor cells. KitL-mobilized myeloid cells homed to primary tumors and pre-metastatic lungs, to give rise to CD11b+c-Kit- cells. Pharmacological 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 pre-irradiated mammary tissue. Pharmacological inhibition of this axis represents a potential therapeutic strategy to prevent metastasis in breast cancer patients with local relapses after radiotherapy.

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 post-radiation metastasis. Experimental Design: 4T1 cells were injected in 20 Gy pre-irradiated mammary tissue, to mimic post-radiation relapses, or in non-irradiated mammary tissue, as control, of immunocompetent BALB/c mice. Molecular, biochemical, cellular, histological analyses, adoptive cell transfer, genetic and pharmacological interventions were performed. Results: Tumors growing in pre-irradiated mammary tissue had reduced angiogenesis, were more hypoxic, invasive and metastatic to lung and lymph nodes compared to control tumors. Increased metastasis involved the mobilization of CD11b+c-Kit+Ly6GhighLy6Clow(Gr1+) myeloid cells through the HIF1-dependent expression of KitL by hypoxic tumor cells. KitL-mobilized myeloid cells homed to primary tumors and pre-metastatic lungs, to give rise to CD11b+c-Kit- cells. Pharmacological 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 pre-irradiated mammary tissue. Pharmacological inhibition of this axis represents a potential therapeutic strategy to prevent metastasis in breast cancer patients with local relapses after radiotherapy.

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 post-radiation metastasis. Experimental Design: 4T1 cells were injected in 20 Gy pre-irradiated mammary tissue, to mimic post-radiation relapses, or in non-irradiated mammary tissue, as control, of immunocompetent BALB/c mice. Molecular, biochemical, cellular, histological analyses, adoptive cell transfer, genetic and pharmacological interventions were performed. Results: Tumors growing in pre-irradiated mammary tissue had reduced angiogenesis, were more hypoxic, invasive and metastatic to lung and lymph nodes compared to control tumors. Increased metastasis involved the mobilization of CD11b+c-Kit+Ly6GhighLy6Clow(Gr1+) myeloid cells through the HIF1-dependent expression of KitL by hypoxic tumor cells. KitL-mobilized myeloid cells homed to primary tumors and pre-metastatic lungs, to give rise to CD11b+c-Kit- cells. Pharmacological 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 pre-irradiated mammary tissue. Pharmacological inhibition of this axis represents a potential therapeutic strategy to prevent metastasis in breast cancer patients with local relapses after radiotherapy.