Date on Master's Thesis/Doctoral Dissertation

12-2017

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, PhD

Committee Chair

Roman, Jesse

Committee Co-Chair (if applicable)

Beverly, Levi

Committee Member

Beverly, Levi

Committee Member

Barve, Shirish

Committee Member

Gupta, Ramesh

Committee Member

Yan, Jun

Author's Keywords

lung cancer; aging; tissue remodeling; fibronectin; lewis lung carcinoma; redox

Abstract

Cancer is largely a disease of the elderly. In the United States alone, 87% of all cancers in 2017 will be diagnosed in individuals aged 50 years or older. Among them, lung cancer is the deadliest, accounting for 1 in 4 cancer deaths. The 5-year survival rate is below 20%, a number which has not changed substantially over the past several decades. This underscores a desperate need for new strategies in prevention, early detection and treatment of this deadly disease. While tobacco use is unquestionably the number one risk factor for the development of lung cancer, the majority of diagnoses occur in individuals with preexisting lung conditions such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, characterized by inflammation and remodeling of the extracellular matrix. Fibronectin is one matrix protein upregulated in these settings. Fibronectin EDA is a splice variant of fibronectin that is increased with aging and has been shown to be a vascular marker for solid tumors and metastases.Moreover, immunization against fibronectin EDA decreases tumor burden and lung metastases in the MMTV-PyMT transgenic model of metastatic mammary carcinoma. In this dissertation, I explore how age-related host factors regulate lung progression. More specifically, I examine how tissue remodeling and aging act in concert, through increased levels of fibronectin EDA, to render the host susceptible to lung cancer progression. This and other work is described in 5 chapters: 1) background and introduction; 2) the role of aging and tissue remodeling in lung cancer; 3) the role of fibroblasts in lung cancer; 4) the role of sex and redox in lung cancer; and 5) summary and discussion. The work described here suggests that age-dependent host factors influence lung cancer progression. Importantly, lung inflammation/tissue remodeling augments pulmonary metastasis in the aging lung, but not in young lungs, through mechanisms involving fibronectin EDA, which perhaps provides a scaffold for tumor cell migration/organization and proliferation. This points to an interplay between lung aging and inflammation/remodeling in lung tumor progression and describes a previously unknown role of fibronectin EDA in lung cancer in the setting of lung injury and aging. Sex also appears to be important, while oxidative stress may play a minor role. Finally, we show that fibroblasts produce factors capable of influencing cancer progression.

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