Metastasis is responsible for a majority of breast cancer deaths. Recent studies estimate that rate of recurrent metastasis of breast cancer is twice as high in patients with asthma compared to those without asthma. High levels of CHI3L1 are found in asthma and breast cancer with even higher levels when these diseases are present together. We hypothesize that CHI3L1- induced pulmonary inflammation generates the proper environment for recruiting circulating breast cancer cells, thus increasing the rate of metastasis to the lung. Thus, inhibiting CHI3L1 is expected to reduce metastasis. We have recently shown that chitin microparticles, the biological binding partner for CHI3L1 decrease pulmonary metastasis and increase survival in mammary tumor-bearing mice. We propose the following two specific Aims: 1) To determine if inflammation associated with CHI3L1 in the lung alters the pulmonary environment to attract circulating breast tumor cells and accelerate metastatic growth and 2) To determine if inhibition of CHI3L1 by either chitin microparticles, anti-CHI3L1 neutralizing antibody or combination of the two decreases tumor metastasis.
These Aims will be addressed by inducing pulmonary inflammation by either ragweed allergen sensitization or by locally expressing CHI3L1 in the lung using AAV-CHI3L1 vector. We will then determine the changes in pulmonary tissue and if it provides the necessary """"""""soil"""""""" for the circulating breast tumor cells. Towards this goal, in vivo imaging for tumor growth and metastasis and related inflammatory response will be determined. We will also determine if inhibition of CHI3L1 significantly reduces tumor growth and metastasis. Significance: Asthma and pulmonary diseases are characterized by increased expression of CHI3L1. Rates of pulmonary inflammation due to pollution, allergies and smoking have been steadily increasing. The studies proposed here will provide a greater understanding of the role of CHI3L1 in enhancing metastasis and the tissue-specific molecular signals that act to exacerbate metastasis under conditions of chronic inflammation. Moreover limiting inflammation by use of molecules that block the activity of CHI3L1 in vivo has the potential to decrease metastasis for many cancer patients also suffering from inflammatory diseases. Combining immunotherapy (anti-CHI3L1 antibody) with the natural bio-product chitin particles could provide novel modes of treatment options for inhibiting metastatic diseases.
Metastasis to the lung is one of the major causes of death in breast cancer patients. Incidence of metastasis is higher in breast cancer patients with chronic pulmonary inflammatory illnesses. Asthma-associated Inflammation plays a key role in the metastasis with expression of mediators such as CHI3L1. Using mice sensitized with ragweed allergen and transduced to overexpress CHI3L1, we will delineate the mechanisms involved in metastasis to the lung. We will determine if inhibition of CHI3L1 decreases metastasis.
|Garcia-Areas, R; Libreros, S; Simoes, M et al. (2017) Suppression of tumor-derived Semaphorin 7A and genetic ablation of host-derived Semaphorin 7A impairs tumor progression in a murine model of advanced breast carcinoma. Int J Oncol 51:1395-1404|
|Libreros, Stephania; Iragavarapu-Charyulu, Vijaya (2015) YKL-40/CHI3L1 drives inflammation on the road of tumor progression. J Leukoc Biol 98:931-6|
|Garcia-Areas, Ramon; Libreros, Stephania; Iragavarapu-Charyulu, Vijaya (2013) Semaphorin7A: branching beyond axonal guidance and into immunity. Immunol Res 57:81-5|
|Libreros, Stephania; Garcia-Areas, Ramon; Iragavarapu-Charyulu, Vijaya (2013) CHI3L1 plays a role in cancer through enhanced production of pro-inflammatory/pro-tumorigenic and angiogenic factors. Immunol Res 57:99-105|
|Libreros, Stephania; Garcia-Areas, Ramon; Shibata, Yoshimi et al. (2012) Induction of proinflammatory mediators by CHI3L1 is reduced by chitin treatment: decreased tumor metastasis in a breast cancer model. Int J Cancer 131:377-86|
|Owen, Jennifer L; Criscitiello, Michael F; Libreros, Stephania et al. (2011) Expression of the inflammatory chemokines CCL2, CCL5 and CXCL2 and the receptors CCR1-3 and CXCR2 in T lymphocytes from mammary tumor-bearing mice. Cell Immunol 270:172-82|