ABSTRACT
Metastasis is the primary cause of mortality in women with breast cancer. Metastasis to the lungs is greater in patients with pulmonary inflammatory illnesses. It is unknown how pre-existing pulmonary inflammation affects mammary tumor progression. We developed a novel breast cancer model in which pulmonary inflammation is induced in mice prior to tumor cell implantation. In the present study, we determined how pre-existing allergen-induced inflammation changes the pulmonary microenvironment to exacerbate tumor metastasis. We showed that pre-existing pulmonary inflammation in mammary tumor bearers is associated with: 1) an increase in growth of the primary tumor and metastasis; 2) an increase in the expression of a glycoprotein known as CHI3L1; and 3) increase in the levels of myeloid populations in their lungs. We also showed that myeloid derived cells from the lungs of allergic tumor bearers produce higher amounts of CHI3L1 than the saline controls. We previously showed that CHI3L1 induces the expression of proinflammatory and protumorigenic molecules. In this study, we show that CHI3L1 knockout tumor bearers with pre-existing allergic pulmonary inflammation had decreased levels of myeloid-derived cells, decreased levels of proinflammatory mediators, and a significant reduction in tumor volume and metastasis compared with the wild-type controls. Pre-existing inflammation and CHI3L1 might be driving the establishment of a premetastatic milieu in the lungs and aiding in the support of metastatic foci. Understanding the role of allergen-induced CHI3L1 and inflammation in tumor bearers and its effects on the pulmonary microenvironment could result in targeted therapies for breast cancer.
ABSTRACT
Elevated levels of chitinase-3-like-1 (CHI3L1) are associated with poor prognosis, shorter recurrence-free intervals and low survival in breast cancer patients. Breast cancer often metastasizes to the lung. We hypothesized that molecules expressed in the "pre-metastatic" lung microenvironment could support the newly immigrant tumor cells by providing growth and angiogenic factors. Macrophages are known to play an important role in tumor growth by releasing pro-angiogenic molecules. Using mouse mammary tumor models, we have previously shown that during neoplastic progression both the mammary tumor cells and splenic macrophages from tumor-bearing mice express higher levels of CHI3L1 compared to normal control mice. However, the role of CHI3L1 in inducing angiogenesis by macrophages at the pulmonary microenvironment to support newly arriving breast cancer cells is not yet known. In this study, we determined the expression of CHI3L1 in bronchoalveolar lavage macrophages and interstitial macrophages in regulating angiogenesis that could support the growth of newly immigrant mammary tumor cells into the lung. Here we show that in vitro treatment of pulmonary macrophages with recombinant murine CHI3L1 resulted in enhanced expression of pro-angiogenic molecules including CCL2, CXCL2, and MMP-9. We and others have previously shown that inhibition of CHI3L1 decreases the production of angiogenic molecules. In this study, we explored if in vivo administration of chitin microparticles has an effect on the expression of CHI3L1 and pro-angiogenic molecules in the lungs of mammary tumor-bearing mice. We show that treatment with chitin microparticles decreases the expression of CHI3L1 and pro-angiogenic molecules in the "metastatic" lung. These studies suggest that targeting CHI3L1 may serve as a potential therapeutic agent to inhibit angiogenesis and thus possibly tumor growth and metastasis.
