Review Cancer Dormancy: A Model of Early Dissemination and Late Cancer Recurrence David P aez, Melissa J. Labonte, Pierre Bohanes, Wu Zhang, Leonor Benhanim, Yan Ning, Takeru Wakatsuki, Fotios Loupakis, and Heinz-Josef Lenz Abstract Cancer dormancy is a stage in tumor progression in which residual disease remains occult and asymptomatic for a prolonged period of time. Dormant tumor cells can be present as one of the earliest stages in tumor development, as well as a stage in micrometastases, and/or minimal residual disease left after an apparently successful treatment of the primary tumor. The general mechanisms that regulate the transition of disseminated tumor cells that have lain dormant into a proliferative state remain largely unknown. However, regulation of the growth from dormant tumor cells may be explained in part through the interaction of the tumor cell with its microenvironment, limitations in the blood supply, or an active immune system. An understanding of the regulatory machinery of these processes is essential for identifying early cancer biomarkers and could provide a rationale for the development of novel agents to target dormant tumor cells. This review focuses on the different signaling models responsible for early cancer dissemination and tumor recurrence that are involved in dormancy pathways. Clin Cancer Res; 18(3); 1–9. Ó2011 AACR. Introduction The major cause of cancer-related deaths is metastatic growth of disseminated tumor cells (DTC) from the primary tumor. Metastatic disease may occur years or even decades after successful treatment of the primary tumor by surgery and adjuvant treatment (1, 2). It has been proposed that this latency period is due to a clinical phenomenon called tumor dormancy. Dormant tumor cells may exist in a quiescent state for many years as solitary tumor cells [i.e., cellular dormancy (3–5)], or as micrometastases whose cellular proliferation is counterbalanced by apoptosis [i.e., tumor mass dormancy (6, 7)]. Consequently, tumor dormancy is a stage in cancer progression in which residual disease is present but is not clinically apparent. During carcinogenesis, tumor cells accumulate genetic alterations that lead to immortalization (loss of function of TP53, retinoblastoma 1 (Rb), p16, and/or gain of telome- rase) and transformation (gain of RAS or BRAF mutations, and ERBB2 amplification). Recent evidence indicates that DTCs have different and fewer genetic alterations compared with primary tumor cells, suggesting the early dissemina- tion of human cancers (8, 9). The general mechanisms that regulate the transition of DTCs that have lain dormant into a proliferative state remain largely unknown. The presence of particular genetic abnormalities acquired by dormant cells may explain the early dissemination of tumor cells, the latency state, and resistance to the conventional therapeu- tics used in the treatment of cancer that target actively dividing cells. However, additional mechanisms, such as the interaction of the tumor cell with its microenvironment, limitations in the blood supply, or an active immune system, can also explain the regulation of the growth of dormant cells. By the time of diagnosis, DTCs can be found in secondary organs such as bone marrow and lymph nodes (10). The detection of circulating tumor cells may explain the dis- semination from primary tumors to target organs (11). The ability of these cells to become tumor metastases is a complex mechanism that may be explained by the tumor dormancy process (Fig. 1). The mechanisms that are involved in tumor dormancy, in relation to tumor recur- rence and sensitivity to therapeutic interventions, represent an area of major interest and investigation. This review discusses the importance of cancer dormancy and how this model is part of disease progression and therapeutic response. Influence of the microenvironment on cancer cell dormancy Recent evidence indicates that the tumor microenviron- ment is a critical regulator of cancer progression (12–15) and a major factor in determining the survival and growth of DTCs at preferential metastatic sites (16). Several of the Authors' Affiliation: Division of Medical Oncology and USC Norris Com- prehensive Cancer Center, Keck School of Medicine, University of South- ern California, Los Angeles, California Corresponding Author: Heinz-Josef Lenz, Sharon A. Carpenter Labora- tory, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033. Phone: 323–865-3967; Fax: 323–865-0061; E-mail: lenz@usc.edu doi: 10.1158/1078-0432.CCR-11-2186 Ó2011 American Association for Cancer Research. Clinical Cancer Research www.aacrjournals.org OF1 Research. on July 16, 2017. © 2011 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst December 9, 2011; DOI: 10.1158/1078-0432.CCR-11-2186