Genes and regulatory pathways involved in persistence of dormant micro-tumors.

Abstract

Micro-tumors can remain dormant for prolonged periods of time before they switch and enter the rapid growth phase. This initial stage in tumor progression is clearly understudied. In spite of high prevalence, significant clinical implications and increased interest by the research community, tumor dormancy is still poorly understood. The topic of tumor dormancy also suffers from a lack of definition and an agreed upon terminology to describe it. Additionally, the number of reproducible experimental models available for studying indolence of human micro-tumors is quite limited. Here, we describe the development of a general class of in vivo models of indolent human tumors and how these models can be used to elucidate molecular and cellular mechanisms involved in the regulation of dormancy. The models consist of human tumor cell lines that form microscopic cancerous lesions in mice. Although these lesions contain viable and fully malignant cancer cells, the tumors do not expand in size but remain occult for prolonged periods until they eventually spontaneously switch and become fast-growing tumors. Consistent with Judah Folkman's vision that tumors will remain occult and microscopic until they acquire the ability to recruit new and functional blood vessels, the dormancy period of the micro-tumors is associated with impaired angiogenic capacity. Such models can be used for dissecting the host and the tumor-derived regulatory mechanisms of tumor dormancy. Understanding the process by which dormant tumors can overcome growth constraints and emerge from dormancy, resuming size expansion, may provide insights into novel strategies to prolong the dormancy state or to block tumor formation in the early stages, before they are physically detected or become symptomatic.