Fig. 2: Dormancy and the metastatic niche.
From: A framework for the development of effective anti-metastatic agents
Metastatic latency is more pronounced for certain types of cancer, notably breast and prostate cancer and melanoma170. The detection of disseminated tumour cells (DTCs) in bone marrow aspirates, obtained long after eradication of the primary tumour, verifies the presence of dormant tumour cells and is predictive of disease recurrence171,172,173. Dormant tumour cells are proposed to exist either as single cells in a state of cell cycle arrest or as small masses of cells that fail to expand into clinically detectable lesions, possibly owing to failure of angiogenesis, balanced rates of proliferation and apoptosis or effective immunosurveillance174. Cells derived from these clusters that are too small to be detected by normal clinical imaging are presumably the source of circulating tumour cells detected in some patients after successful treatment of the primary tumour. The metastatic niche is likely to vary between different organs, reflecting the tissue-specific nature of the microenvironment in which the DTC is located; extensive crosstalk occurs between the tumour cells, stromal cells and extracellular matrix components of the niche. Various niches have been proposed, including the perivascular niche associated with the vasculature22, the haematopoietic stem cell niche of the bone marrow175 and the osteoblastic niche in bone176. The factors that maintain tumour cell dormancy in these niches are starting to be unravelled, with different extracellular matrix components, cytokines and other proteins being implicated for different cancer types and niches. Far less is understood about how dormancy is broken, which could occur following failure of immunosurveillance, in response to inflammation triggered by trauma or an infection or perhaps as a result of ageing-related deficiencies in tissue homeostasis. With regard to therapy, the challenge is to decide whether the aim should be to retain the DTCs in a dormant state or, instead, to disrupt their niche and dormancy, thereby rendering them susceptible to apoptotic or anoikic death and/or to chemotherapy.
