Framework models of tumor dormancy from patient-derived observations
Introduction
‘Which grain will grow and which will not?’ belongs to the fundamental questions of cancer research. Since disseminated tumor cells (DTCs) can be routinely detected in the bone marrow or lymph nodes of cancer patients long before manifestation of metastases [1], they have been considered as metastasis precursor/founder cells and as material correlate of minimal residual disease and clinical tumor dormancy. Indeed, their analysis may shed some light into the field of tumor dormancy, which suffers from many speculations and an ill-defined language. By strictly separating patient-derived and model-derived data, I try to specify the meaning of tumor dormancy and what is needed for a better understanding.
Section snippets
History and semantics of tumor dormancy
The Australian pathologist Rupert Willis originally coined the term ‘dormant tumour cells’ having analyzed the metastatic spread of human cancers in autopsy studies. In 1934 he wrote (p. 114) ‘When long-delayed metastatic tumours appear in a patient in whom there is no local recurrence of the extirpated primary growth, it is clear that the secondary growths must have arisen from tumour-emboli disseminated from the primary growth before its removal. The neoplastic cells must have lain dormant in
The prevalence of clinical dormancy is unknown
This notion becomes evident, when we compare 20-year follow-up data from different periods in medical history. For example, 65% of all breast cancer patients died within 20 years from the disease between 1945 and 1965 (Figure 1a). Of these, 69% died within the first five years and 31% between 5 and 20 years after surgery. Thus, 31% of patients would conform the clinical dormancy definition at that time [6]. Of breast cancer patients that were diagnosed between 1988 and 1997, 47% died within 20
A non-productive state of DTCs is frequent
On the other hand, Willis’ suggestion that the growth of disseminated cancer cells may be restrained is supported by various observations. The first line of evidence stems from the analysis of DTCs in bone marrow. Detection of DTCs by cytokeratin markers at the time point of initial surgery, although only few cells are detected per sample, is associated with poor outcome for a variety of cancers, including prostate cancer [23, 24•]. However, when prostate cancer patients whose bone marrow did
Mechanisms of dormancy
The current knowledge about dormancy mechanisms has been reviewed in detail repeatedly [37, 38, 39, 40, 41] and therefore the task here is to categorize the principles underlying the non-productive state of DTCs.
Growth restraints by the ectopic site
Willis’ suggestion of microenvironmental growth restraints awaits its detailed elucidation for the human disease. Unfortunately, in the majority of studies, while interesting and important, dormancy was generated by placing human cancer cells either in a Petri dish or in a murine environment and thereby cross-species incompatibilities were investigated (including incompatibilities of ECM components, cellular interactions and of growth factors and cytokines) or dormancy by artificial
Quiescence, autophagy, hibernation
Despite the difficulties to pinpoint cellular and molecular interactions that are involved in the establishment of dormancy, Hadfield's ‘temporary mitotic arrest’ has been elucidated down to the level of specific pathways and genetic programs. In their pioneering work Aguirre-Ghiso and Ossowski used the human HEp3 head and neck cancer model. They found that the extracellular signal-regulated kinase (ERK)MAPK/p38SAPK activity ratio predicts whether the cells will proliferate or enter a state of
Dormancy or homeostasis?
Others have added to Willis’ dormancy definition the dynamic equilibrium of active proliferation and apoptosis until tumor cells succeed to induce tumor angiogenesis [64, 65, 66] and dormancy resulting from immunosurveillance [67•, 68]. Angiogenic and immune mechanisms of dormancy have in common that they may regulate primary and metastatic growth. In fact, the molecular genetic analysis of DTCs revealed that DTCs display often different and also fewer genetic alterations than primary tumor
Conclusions
I started from what I believe is the origin of the term tumor dormancy, the definitions of Willis and Hadfield. They specify tumor dormancy as a process involving growth restrains exerted by the ectopic tissue leading to reversible mitotic arrest. I further suggested refraining from the term ‘clinical dormancy’ until we can determine growth kinetics of primary tumors and metastasis of individual patients and differentiate disease courses with patient-specific ‘regular’ from protracted
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
I am very grateful to Stefanie Pausch and Matthias Maneck for help with the figures and to Miodrag Guzvic and Nikolas Stoecklein for critical reading of the manuscript. This work was supported by the Bavarian State Ministry of Sciences, Research and the Arts.
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