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A Study of Genetic Alterations in Cancer Progression

Ramchandani, Divya
http://orcid.org/0000-0003-3026-9345
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439295281

Abstract Details

2015, PhD, University of Cincinnati, Pharmacy: Pharmaceutical Sciences/Biopharmaceutics.
Cancer is one of the most complex diseases, the cause of which is only partially understood and that makes it difficult to identify proper strategies for its treatment. In simple terms, it is defined as an uncontrolled growth of abnormal cells in the body that may spread from their primary site of origin to distant, secondary organs in the body. This spreading of cancer, called cancer metastasis, makes its treatment even more difficult and is responsible for the majority of deaths due to the disease. A multitude of genetic alterations are responsible for tumor invasion and metastasis that form the life-threatening aspect of cancer. There is an incomplete understanding of specific genetic targets for tumor metastasis. Genetic alterations leading to activation of oncogenes and consecutively metastasis genes leads to tumorigenesis and tumor progression, respectively. While oncogenes have the potential to initiate tumor cell growth and promote their survival, it is the metastasis genes that govern tumor progression and its aggressiveness. Metastasis Genes undergo genetic alteration by two mechanisms: 1. Aberrant Expression; and 2. Alternative Splicing. Both osteopontin (OPN) and tissue factor (TF) are metastasis genes that are known to influence tumor aggressiveness and cause a worsened prognosis in cancer patients. Alternative splice variants of OPN and their roles in cancer progression have been well characterized (Chae et al., 2009; He et al., 2006). However, the role of OPN genetic polymorphisms in tumor aggressiveness remains unknown. Polymorphism, specifically in the promoter region of a gene, affects the expression levels of its protein product, and hence, may influence the various functions. Via single nucleotide polymorphism (SNP) analysis of DNA samples from breast cancer patients, we have identified an important polymorphic site in the promoter region of OPN gene that has significant association with breast cancer aggressiveness. The second mechanism by which genetic alterations affect metastasis genes is via alternative splicing (Brinkman, 2004). After transcription, the primary transcript may undergo splicing to form diverse mRNAs, which may have different properties than the original transcription product of the gene. The primary transcript of Tissue Factor, the main trigger of coagulation, undergoes alternative splicing that yields a secreted variant, termed asTF (alternatively spliced Tissue Factor). asTF does not have a physiologic function in hemostasis, but its expression positively correlates with advanced tumor stages. Since the expression of asTF is prominent in the advanced stages of cancer that are more hypoxic, acidic and nutrient-deficient, we aimed to analyze the mechanism by which asTF might be contributing to tumor progression in such hypoxic conditions. Carbonic anhydrase IX (CAIX) is a novel downstream mediator of the asTF effects in pancreatic cancer progression under hypoxic conditions that model advanced stage tumor micro-environment. This research has laid the groundwork for the study of the two types of genetic alterations observed in metastasis gene, in the context of OPN and asTF. We hope it will play a significant role in the development of more robust strategies for targeting these genetic anomalies in cancer.
Georg Weber, M.D. Ph.D. (Committee Chair)
Vladimir Bogdanov, Ph.D. (Committee Member)
Pankaj Desai, Ph.D. (Committee Member)
Jiukuan Hao, Ph.D. (Committee Member)
Sohaib Khan, Ph.D. (Committee Member)
112 p.
Oncology
Osteopontin; Tissue Factor; Metastasis; Polymorphism; Hypoxia; Splicing

Recommended Citations

Citations

  • Ramchandani, D. (2015). A Study of Genetic Alterations in Cancer Progression [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439295281

    APA Style (7th edition)

  • Ramchandani, Divya. A Study of Genetic Alterations in Cancer Progression. 2015. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439295281.

    MLA Style (8th edition)

  • Ramchandani, Divya. "A Study of Genetic Alterations in Cancer Progression." Doctoral dissertation, University of Cincinnati, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439295281

    Chicago Manual of Style (17th edition)

ucin1439295281
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This open access ETD is published by University of Cincinnati and OhioLINK.