Hypoxia and tumor dormancy: Can the two tango?

Majority of cancer patients die of metastatic disease that can develop decades after primary tumor removal. During this period the disseminated tumor cells (DTCs) may stop proliferating and survive in a dormant state, a phenomenon also referred to as minimal residual disease (MRD). MRD is a well-known clinical phenomenon and studying the mechanisms behind this stage of tumor progression specifically the contribution of the microenvironments are areas of active investigation. Hypoxic microenvironments, which result from a decrease in oxygen levels, are common during tumor progression, but its role in the induction and maintenance of the dormant state remains unclear. This chapter focuses on some of the experimental as well as theoretical evidence supporting how tumor hypoxia both in the primary tumor as well as at target organ sites can influence disseminated tumor cells (DTCs) to enter dormancy. Furthermore, the interplay between hypoxic and the unfolded protein response (UPR) signaling in promoting the survival of dormant tumor cells, which is critical for both long term survival as well as therapy resistance is also reviewed. Lastly, the chapter emphasizes on the parallels between the concept of tumor dormancy and cancer stem cells (CSCs) and the overlapping roles of hypoxia mediated signals in the maintenance of quiescence of CSCs as well as and dormant tumor cells. This information is essential to design urgently needed therapeutic strategies aimed at either maintaining these DTCs in a dormant state or eradicating them before they progress to overt metastasis.