Abstract
BackgroundMechanisms that preclude lung metastasis are still barely understood. The possible consequences of allergic airways inflammation on cancer dissemination were studied in a mouse model of breast cancer.MethodsBalb/c mice were immunized and daily exposed to ovalbumin (OVA) from day 21. They were subcutaneously injected with 4T1 mammary tumor cells on day 45 and sacrificed on day 67. Lung metastases were measured by biophotonic imaging (IVIS® 200 Imaging System) and histological measurement of tumor area (Cytomine software). Effects of CCL11 were assessed in vivo by intratracheal instillations of recCCL11 and in vitro using Boyden chambers. CCR3 expression on cell surface was assessed by flow cytometry.ResultsThe extent of tumor metastases was significantly higher in lungs of OVA-exposed mice and increased levels of CCL11 expression were measured after OVA exposure. Migration of 4T1 cells and neutrophils was stimulated in vitro and in vivo by recCCL11. 4T1 cells and neutrophils express CCR3 as shown by flow cytometry and a selective CCR3 antagonist (SB-297006) inhibited the induction of 4T1 cells migration and proliferation in response to recCCL11.ConclusionsAllergic inflammation generated by exposure to allergens triggers the implantation of metastatic cells from primary breast tumor into lung tissues plausibly in a CCL11–CCR3-dependent manner. This indicates that asthma related inflammation in lungs might be a risk factor for lung metastasis in breast cancer patients.
Highlights
Mechanisms that preclude lung metastasis are still barely understood
It has been hypothesized that this chronic condition might be a risk factor in developing lung cancer [3], especially in non-smokers [4], and that it might lead to metastatic dissemination
Allergen exposure promotes migration of breast cancer cells to the lungs In order to analyze the effects of inflammation elicited by allergen exposure on metastatic dissemination of tumor cells, Balb/c mice were sensitized and exposed to inhaled OVA or Phosphate Buffered Saline (PBS) from day 21 to 67 and were subcutaneously (s.c) injected with 4T1 cancer cells on day 45 (Fig. 1a)
Summary
Mechanisms that preclude lung metastasis are still barely understood. The possible consequences of allergic airways inflammation on cancer dissemination were studied in a mouse model of breast cancer. Different cytokines are therapeutic targets in asthma with different treatments on the market targeting IL5 or IL4 and IL13 receptor and other products in development that comprise CXCR2 antagonists or low molecular weight chemicals that antagonize CCL11 receptor, cysteine-cysteine chemokine receptor-3 (CCR3) [19,20,21]. As these potent medications allow the control of severe forms of asthma, it is important to unveil any potential link between asthma-related inflammation and possible mechanisms triggering pulmonary metastases
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