Translational studies of epithelial cancer

Abstract

Tumors stemming from specialized epithelial cells cause the most common cancer types and are among the leading causes of death in the western world. Although great strides have been made in early cancer detection, defining prognostic factors, and improving survival with novel treatments, cancers such as colorectal cancer and prostate cancer are incurable in their advanced stages. In the work presented in this thesis, we aim to explore the biological underpinnings of tumor initiation and progression and determine novel pharmaceutical treatment strategies against epithelial cancer. We do so by combining preclinical methodologies of cell culture and animal models of disease with epidemiological studies of population and patient cohorts. EphB tyrosine kinase receptors promote intestinal tumor proliferation via the tyrosine-protein kinase Abl1 (Abl kinase) (Genander et al., 2009; Holmberg et al., 2006). In paper I, we find that the Abl kinase inhibitor imatinib blocks EphB receptor regulated tumor initiation and growth in mouse models of early-stage intestinal tumors, reduces proliferation in ex vivo human adenomas and prolongs survival of tumor bearing mice. We propose imatinib as a possible prevention and early treatment strategy for people prone to develop intestinal adenomas. In paper II, we explore the immune system and antiviral immunity as potential markers of prostate cancer prognosis. In prostate cancer patients, the Human Leukocyte Antigen (HLA) alleles HLA-A*02:01 and HLA-A*11 are associated with poor disease recurrence free survival after prostatectomy. Immunity to the human herpesvirus cytomegalovirus (CMV) in prostate tumors is associated with particularly poor disease recurrence free survival in HLA-A*02:01+ prostate cancer patients. In paper III, we find that CMV commonly chronically infects epithelium in the healthy and malignant prostate, prostate cancer metastases and prostate cancer cell lines. Experimental and therapeutic inhibition of CMV in in vitro and in vivo models of prostate cancer reveal that CMV promotes its viability and growth and propose that CMV targeting drugs can be repurposed against prostate cancer. In paper IV, we describe that CMV seropositivity is associated with high CMV abundance in healthy and malignant prostate. Studying a large prospective population cohort, we find that CMV seropositivity is not associated with prostate cancer incidence but is associated with increased risk of dying from prostate cancer after receiving a prostate cancer diagnosis.