Framework models of tumor dormancy from patient-derived observations

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Unusually long latency periods between the treatment of primary tumors and metastatic recurrences are commonly thought to prove the existence and relevance of clinical tumor dormancy. However, careful consideration of disease courses and cancer growth rates leads to the conclusion that clinical dormancy may be everything from non-existent to much more frequent than originally thought. On the other hand, cellular dormancy defined as a non-productive state of disseminated tumor cells is very frequent, while homeostatic mechanisms such as angiogenic and immunological control contribute to the chronicity of cancer. This review attempts to provide a conceptual framework for the study of dormancy, which may guide clinical and experimental research.

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.

References (76)

  • R.A. Willis

    The Spread of Tumours in the Human Body

    (1934)
  • G. Hadfield

    The dormant cancer cell

    Br Med J

    (1954)
  • M. Nielsen et al.

    Breast cancer and atypia among young and middle-aged women: a study of 110 medicolegal autopsies

    Br J Cancer

    (1987)
  • H. Joensuu et al.

    Comparison of breast carcinomas diagnosed in the 1980s with those diagnosed in the 1940s to 1960s

    BMJ

    (1991)
  • World Wide Web URL:...
  • W. Friedl et al.

    The long-term prognosis of breast cancer. Retrospective study of 973 patients

    Langenbecks Arch Chir

    (1992)
  • T.G. Karrison et al.

    Dormancy of mammary carcinoma after mastectomy

    J Natl Cancer Inst

    (1999)
  • N.J. Crowley et al.

    Late recurrence of malignant melanoma. Analysis of 168 patients

    Ann Surg

    (1990)
  • G. Hansel et al.

    Late recurrence (10 years or more) of malignant melanoma in south-east Germany (Saxony). A single-centre analysis of 1881 patients with a follow-up of 10 years or more

    J Eur Acad Dermatol Venereol

    (2010)
  • J.A. Leman et al.

    Late (>10 years) recurrence of melanoma: the Scottish experience

    Br J Dermatol

    (2003)
  • A. Peters et al.

    First melanoma metastases after 10 years and more of remission

    Hautarzt

    (1997)
  • M.H. Schmid-Wendtner et al.

    Late metastases of cutaneous melanoma: an analysis of 31 patients

    J Am Acad Dermatol

    (2000)
  • H.M. Shaw et al.

    Late relapse from cutaneous stage I malignant melanoma

    Arch Surg

    (1985)
  • H. Tsao et al.

    Ultra-late recurrence (15 years or longer) of cutaneous melanoma

    Cancer

    (1997)
  • F.M. Blows et al.

    Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies

    PLoS Med

    (2010)
  • P. Wirapati et al.

    Meta-analysis of gene expression profiles in breast cancer: toward a unified understanding of breast cancer subtyping and prognosis signatures

    Breast Cancer Res

    (2008)
  • H. Weedon-Fekjaer et al.

    Breast cancer tumor growth estimated through mammography screening data

    Breast Cancer Res

    (2008)
  • C.A. Klein

    Parallel progression of primary tumours and metastases

    Nat Rev Cancer

    (2009)
  • R. Demicheli

    Tumour dormancy: findings and hypotheses from clinical research on breast cancer

    Semin Cancer Biol

    (2001)
  • R. Demicheli et al.

    Time distribution of the recurrence risk for breast cancer patients undergoing mastectomy: further support about the concept of tumor dormancy

    Breast Cancer Res Treat

    (1996)
  • S. Riethdorf et al.

    Review: biological relevance of disseminated tumor cells in cancer patients

    Int J Cancer

    (2008)
  • D. Weckermann et al.

    Perioperative activation of disseminated tumor cells in bone marrow of patients with prostate cancer

    J Clin Oncol

    (2009)
  • S. Meng et al.

    Circulating tumor cells in patients with breast cancer dormancy

    Clin Cancer Res

    (2004)
  • G. Riethmuller et al.

    Early cancer cell dissemination and late metastatic relapse: clinical reflections and biological approaches to the dormancy problem in patients

    Semin Cancer Biol

    (2001)
  • J.F. Buell et al.

    Donor transmitted malignancies

    Ann Transplant

    (2004)
  • J.F. Buell et al.

    Transmission of donor cancer into cardiothoracic transplant recipients

    Surgery

    (2001)
  • E.S. Woodle et al.

    Prostate cancer prior to solid organ transplantation: the Israel Penn International Transplant Tumor Registry experience

    Transplant Proc

    (2005)
  • R.M. MacKie et al.

    Fatal melanoma transferred in a donated kidney 16 years after melanoma surgery

    N Engl J Med

    (2003)
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