Dormancy in cancer

Abstract

The idea of tumor dormancy originated from clinical findings that recurrence of cancer occurs several years or even several decades after surgical resection of the primary tumor. Tumor mass dormancy was proposed as a model, where there is equal balance between increases in the number of cancer cells by proliferation and decreases as a result of cell death. Tumor mass dormancy includes angiogenic dormancy and immune-mediated dormancy. Another emerging type of tumor dormancy is cellular dormancy in which cancer cells are in a quiescent state. Cellular dormancy is induced by cues such as the extracellular matrix environment, metastatic niches, a hypoxic microenvironment, and endoplasmic reticulum stress. Even the oncogenic pathways, on which active cancer cells depend for survival and growth, are suppressed in the dormant state. As tumor dormancy is one of the mechanisms of resistance against various cancer therapies, targeting dormant cancer cells should be considered for future treatment strategies.

Figure 1

Tumor mass dormancy and cellular dormancy. The balance between the growth and death of cancer cells is illustrated. When the balance between growth and death is equal, the tumor is in tumor mass dormancy. In cellular dormancy, both growth and death are minimal. The underlying mechanisms are indicated

Figure 2

Cancer cells in hypoxic regions are inactive. Immunohistochemistry of a mouse xenograft tumor, generated by s.c. injection of HCT116, a colon cancer cell line (reprinted from Okuyama et al54). Primary antibodies are indicated for each panel. Pimonidazole staining (green) represents hypoxic regions; CD31, blood vessels; BrdU, proliferation; pS6, mTORC1 activity. Areas distant from the blood vessels, including the pimonidazole‐positive regions, are negative for BrdU, pS6, and MYC. Scale bar, 100 μm

Figure 3

Mechanisms of cellular dormancy. There are various mechanisms underlying cellular dormancy. Black thin arrows, stimulation; blue thin arrows, intracellular signal; thick orange and blue arrows, up and down regulation, respectively, in terms of protein levels or activation of the molecule or the signal. EGFR, epidermal growth factor receptor; ER, endoplasmic reticulum; HER, human epidermal growth factor receptor; HIGD1A, hypoxia‐inducible gene domain family member 1A; mut, active mutant; P, phosphorylation; TGFβ2, transforming growth factor beta‐2

Figure 4

Glycolysis and oxidative phosphorylation in dormant cancer cells. Activation status of the metabolic pathways is expressed as thickening of arrows. Amount of ATP produced is illustrated as the number of ATP molecules