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Chitinase-3 like-protein-1 CHI3L1 expression associated with pulmonary inflammation accelerates breast cancer metastasis
Title
Chitinase-3 like-protein-1 CHI3L1 expression associated with pulmonary inflammation accelerates breast cancer metastasis.
Creator
Libreros, Stephania, Areas, Ramon Garcia, Iragavarapu-Charyulu, Vijaya, Graduate College
Abstract/Description
Disseminated metastasis accounts for a majority of breast cancer deaths. Recently, elevated serum levels of a glycoprotein known as chitinase-3 like-protein-1 CHI3L1 has been correlated with poor prognosis in both breast cancer and asthmatic patients. We have combined mouse models of breast cancer and pulmonary inflammation to determine if CHI3L1 associated pulmonary inflammation accelerates metastasis. We found that allergic pulmonary inflammation significantly enhances primary tumor growth...
Show moreDisseminated metastasis accounts for a majority of breast cancer deaths. Recently, elevated serum levels of a glycoprotein known as chitinase-3 like-protein-1 CHI3L1 has been correlated with poor prognosis in both breast cancer and asthmatic patients. We have combined mouse models of breast cancer and pulmonary inflammation to determine if CHI3L1 associated pulmonary inflammation accelerates metastasis. We found that allergic pulmonary inflammation significantly enhances primary tumor growth in 4T1, 4T07 and 67NR mammary tumors by 10- fold, while decreasing survival. 4T1 tumor bearers with allergic pulmonary inflammation showed a 100-fold increase in metastatic tumor formation. We also assessed CHI3L1 levels and myeloid cells in the lungs of wild type and CHI3L1 knockout mice with allergic pulmonary inflammation and 4T1 mammary tumors. CHI3L1 levels were higher in the lungs of mammary tumor bearers with allergic pulmonary inflammation and correlated with increased metastasis. Wild type mammary tumor bearers with allergic inflammation had higher numbers of myeloid cells in the lungs in comparison to CHI3L1 knockout tumor bearers with allergic pulmonary inflammation. CHI3L1 knockout mice tumor bearers had significantly fewer myeloid cells in the lungs, decreased tumor growth and metastasis, along with increased survival. We propose that increased CHI3L1 in the lungs attracts myeloid cells that promote tumor growth and breast cancer metastasis.
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Date Issued
2014
PURL
http://purl.flvc.org/fau/fd/FA00005832
Format
Document (PDF)
A novel immunosuppressive pathway mediated by chitinase-3-like-1 protein in a model of breast cancer
Title
A novel immunosuppressive pathway mediated by chitinase-3-like-1 protein in a model of breast cancer.
Creator
Libreros, Stephania, Garcia-Areas, Ramon A., Iragavarapu-Charyulu, Vijaya, Graduate College
Date Issued
2011-04-08
PURL
http://purl.flvc.org/fcla/dt/3164613
Subject Headings
Immunosuppression, Chitinase, Breast --Cancer
Format
Document (PDF)
Hypoxia Inducible Factor-Alpha Promotes Expression of Pro-tumorigenic Semaphorin7A in Mammary Tumor Cells
Title
Hypoxia Inducible Factor-Alpha Promotes Expression of Pro-tumorigenic Semaphorin7A in Mammary Tumor Cells.
Creator
Karram, Joseph P., Garcia-Areas, Ramon A., Libreros, Stephania, Graduate College, Castro, C., Keating, Patricia, Iragavarapu-Charyulu, Vijaya
Abstract/Description
It is estimated that one in eight women will be diagnosed with breast cancer. Developing an understanding of the tumor microenvironment is critical for developing treatments for breast cancer patients. It has been well established that hypoxia, or a lack of oxygen, is fundamental in creating a microenvironment that enables metastasis via eliciting angiogenic processes. Poorly differentiated blood vessels can fashion an oxygen-deprived microenvironment that triggers the expression of...
Show moreIt is estimated that one in eight women will be diagnosed with breast cancer. Developing an understanding of the tumor microenvironment is critical for developing treatments for breast cancer patients. It has been well established that hypoxia, or a lack of oxygen, is fundamental in creating a microenvironment that enables metastasis via eliciting angiogenic processes. Poorly differentiated blood vessels can fashion an oxygen-deprived microenvironment that triggers the expression of transcription factor Hypoxia Inducible Factor alpha HIF-1alpha that in turn can up regulate genes mediating a protumor effect. Our laboratory has discovered that mammary tumors express Semaphorin7a SEMA7A, a HIF-1alpha inducible protein. This study’s objective is to delineate the mechanism for hypoxia induction in mammary cells. Cobalt Chloride CoCl2 was used to mimic hypoxia in mammary tumor cell cultures. Flow cytometry was used to determine HIF-1alpha activity in the mammary cells. Benign EpH4 mammary cells expressing low SEMA7A greatly increased its expression after response to hypoxic stimuli as determined by qPCR and SEMA7A-specific ELISA. Pretreatment of EpH4 cells with a HIF-1alpha inhibitor Chemotin blocked induction of SEMA7A. Paradoxically, CoCl2 did not raise expression in the highly metastatic 4T1 cells which experience high levels of SEMA7A. Treatment of 4T1 cells with Chemotin under normoxic conditions inhibit HIF-1alpha activity and decrease SEMA7A levels. Determining the role of SEMA7A in the hypoxia axis could further elucidate novel pathways in breast cancer, suggesting that malignant tumor cells can utilize HIF-1alpha in a hypoxic independent manner.
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Date Issued
2015
PURL
http://purl.flvc.org/fau/fd/FA00005887
Format
Document (PDF)
Exploring the role of CHI3L1 in “pre-metastatic” lungs of mammary tumor-bearing mice
Title
Exploring the role of CHI3L1 in “pre-metastatic” lungs of mammary tumor-bearing mice.
Creator
Libreros, Stephania, Garcia-Areas, Ramon A., Keating, Patricia, Carrio, Roberto, Iragavarapu-Charyulu, Vijaya
Date Issued
2013
PURL
http://purl.flvc.org/fau/fd/FAUIR000157
Format
Citation
Semaphorin7A promotes tumor growth and exerts a pro-angiogenic effect in macrophages of mammary tumor-bearing mice
Title
Semaphorin7A promotes tumor growth and exerts a pro-angiogenic effect in macrophages of mammary tumor-bearing mice.
Creator
Garcia-Areas, Ramon A., Libreros, Stephania, Amat, Samantha, Keating, Patricia, Carrio, Roberto, Robinson, Phillip, Blieden, Clifford, Iragavarapu-Charyulu, Vijaya
Date Issued
2014
PURL
http://purl.flvc.org/fau/fd/FAUIR000158
Format
Citation
Investigating the Role of CHI3L1 in Promoting Tumor Growth and Metastasis Using Mammary Tumor Models
Title
Investigating the Role of CHI3L1 in Promoting Tumor Growth and Metastasis Using Mammary Tumor Models.
Creator
Libreros, Stephania, Iragavarapu-Charyulu, Vijaya, Florida Atlantic University, Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description
Metastasis is the primary cause of mortality in women with breast cancer. Recently, elevated serum levels of a glycoprotein known as chitinase-3 likeprotein- 1 (CHI3L1) has been correlated with poor prognosis and shorter survival of patients with cancer and inflammatory diseases. The biological and physiological functions of CHI3L1 in tumor progression have not yet been elucidated. In this document, we describe the role of CHI3L1 in tumor growth and metastasis and its relationship with...
Show moreMetastasis is the primary cause of mortality in women with breast cancer. Recently, elevated serum levels of a glycoprotein known as chitinase-3 likeprotein- 1 (CHI3L1) has been correlated with poor prognosis and shorter survival of patients with cancer and inflammatory diseases. The biological and physiological functions of CHI3L1 in tumor progression have not yet been elucidated. In this document, we describe the role of CHI3L1 in tumor growth and metastasis and its relationship with inflammation. Using well-established models of breast cancer, we show that CHI3L1 is increased in the serum of tumor bearing mice. We found that CHI3L1 levels are increased at both the “pre-metastatic” and “metastatic stage” and that tumor cells, splenic, alveolar and interstitial macrophages; and myeloid derived population produce CHI3L1. Furthermore, we demonstrated that CHI3L1 has an inhibitory role on the expression of interferon-gamma (IFN γ) by T cells, while enhancing the production of pro-inflammatory mediators by macrophages such as Cchemokine ligand 2 (CCL2/MCP-1), Chemokine CX motif ligand 2 (CXCL2/IL-8) and matrix metalloproteinase-9 (MMP-9), all of which promote tumor growth and metastasis. We demonstrated that in vivo treatment of tumor-bearing mice with chitin microparticles, a TH1 adjuvant and a substrate for CHI3L1, promoted immune effector functions with increased production of IFN-γ but decreased CCL2/MCP-1, CXCL2/IL-8 and MMP-9 expression by splenic and pulmonary macrophages. Significantly, in vivo administration of chitin microparticles decreased tumor growth and pulmonary metastasis in mammary tumor bearing mice. These results suggest that CHI3L1 may play a role in tumor progression. Inflammation plays a pivotal role during tumor progression and metastasis by promoting the production of pro-inflammatory molecules such as CHI3L1. However, little is known about how CHI3L1 expression can affect secondary sites to enhance metastasis. In these studies, we demonstrated that CHI3L1 alters the cellular composition and inflammatory mediators that aid in the establishment of a metastatic niche for the support of infiltrating tumor cells leading to accelerated tumor progression. Since previous studies showed that CHI3L1 modulates inflammation, we determined the role of CHI3L1 in the context of pre-existing inflammation and metastasis. We found that CHI3L1 deficient mice with preexisting inflammation had decreased pro-inflammatory mediators, and significant reduction in tumor volume and metastasis compared to wild type controls. Preexisting inflammation and CHI3L1 may be driving the establishment of a premetastatic milieu in the lungs and aiding in the establishment of metastasis. Understanding the role of CHI3L1 in inflammation during tumor progression could result in the design of targeted therapies for breast cancer patients.
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Date Issued
2015
PURL
http://purl.flvc.org/fau/fd/FA00004517, http://purl.flvc.org/fau/fd/FA00004517
Subject Headings
Biopharmaceutics, Breast -- Cancer -- Etiology, Breast -- Cancer -- Molecular aspects, Cell differentiation, Chitinase, Glycoproteins -- Metabolism, Inflammation, Mice as laboratory animals
Format
Document (PDF)