DDRs in Healthy and Cancerous Reproductive Systems

Abstract

Discoidin domain receptors (DDRs) are uniquely positioned to function as sensors for extracellular matrix (ECM) and to regulate a wide range of cell functions from migration and proliferation to cytokine secretion and ECM homeostasis/remodeling. While activation of DDRs by ECM collagens is required for normal development and tissue homeostasis, aberrant activation and function of these receptors following injury or in disease is detrimental. Both DDRs are indicated to play key roles in development and metastasis of various types of cancer. In spite of this, the mechanisms whereby DDRs contribute to tumor formation and cancer progression are poorly understood. Among reproductive system cancers, epithelial ovarian cancer (EOC) and prostate cancer (PCa) result in high rates of morbidity and mortality. In EOC and PCa, atypical expressions of DDRs are indicated to function in malignancy and metastasis. The molecular mechanisms underlying how DDRs contribute to these and other pathologies need to be understood to find new markers and for development of therapeutic agents for treatment of disease. This is particularly the case for EOC in which mechanisms explaining the atypically high levels of DDR1 at initial and late stages of disease have not been described. We first outline studies showing an essential role for DDR2 in steroidogenesis and gamete development in ovary and testes. We then focus on what is known on the role of DDR1 and DDR2 in PCa and DDR1 in EOC. Finally, we speculate on possible functions DDR1 could be playing in different stages of EOC disease. Interactions between ECM proteins and cell surface receptors are well known to play key roles in regulation of cell behavior and determining physiological function. The switch from DDR2 expression in healthy ovaries to that of DDR1 in initial and late stages of EOC disease provides an experimental system to investigate to what extent ECM and DDR signaling enables malignant transformation.