Dormancy tumor

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The English term Tumor Dormancy (literally ' tumor rest', dormancy = dormancy , 'resting state') is used in oncology to describe the phase of a malignant tumor in which growth has stopped and the tumor remains in an apparently “sleeping” state. Although tumor cells are present in this resting phase, tumor progression is clinically imperceptible. This resting phase, in which the cancer cells are below the detection threshold of conventional diagnostics , can last from months to several decades .

Terms in German, such as tumor sleep or sleeping tumor , have hardly been established in the literature so far.

Pathology and prevalence

The cause of Tumor Dormancy can in principle be a halted cell cycle or a dynamic balance between cell proliferation (new formation of cells; in the example cancer cells) and apoptosis (programmed cell death). Tumor dormancy is defined as the time between carcinogenic transformation and the onset of unstoppable progressive tumor growth.

There is a body of evidence to suggest that microscopic, dormant tumors are extremely common in otherwise healthy individuals. Due to their small size, their non-invasive properties and the lack of symptoms , these tumors go undetected in most cases. It was only in the 1990s that it was recognized that the Dormancy tumor is much more common than originally assumed. When accident victims are autopsied, microscopic tumors can be found in most of these people. The fact that clinically relevant cancers develop from this in very few cases is attributed to several mechanisms. Among other things, the body's own immune monitoring , a blockage or the inability to form new blood vessels ( angiogenesis ) and an exit from the cell cycle are discussed . The processes underlying a Dormancy tumor are still largely unclear. A more precise knowledge of the processes that can bring about this effect can have a considerable influence on the diagnosis and treatment of cancer in the future.

Angiogenesis is an important factor influencing the Dormancy tumor. For the growth of a solid tumor beyond a volume of 1 to 2 mm³ the formation of new blood vessels is necessary so that the tumor cells can be adequately supplied with nutrients and oxygen. Without the ability to develop new blood vessels for supply, these non-angiogenic neoplasms remain limited to a symptom-free and clinically irrelevant size. The supply of nutrients is guaranteed by diffusion . The high rate of proliferation of the degenerate cells is offset by an increase in the number of dying cancer cells. A dynamic equilibrium is established between new and dying cells, which means that tumor growth stops. The formation of new vessels is regulated by various messenger substances . VEGF ( Vascular Endothelial Growth Factor ) and FGF-1 ( acidic Fibroblast Growth Factor ) and FGF-2 ( basic Fibroblast Growth Factor ) are known as activators of angiogenesis . In contrast, for example, α-interferon , platelet factor 4 (PF4) and angiostatin are inhibitors of angiogenesis. According to the model, inhibitors predominate or there is a balance between the two sides during the tumor dormancy phase. If the balance shifts in the direction of the activators, blood vessels develop to supply the tumor. This balance is shifted by genetic changes in the tumor cells during tumorigenesis , which upregulate the expression of proangiogenic factors. In this context one speaks of an angiogenic switch ("angiogenic switch"), in which the tumor changes from the avascular to the vascular state.

However, not all tumor cells change to the vascular state. Only about 4 to 10% of the cells correspond to the angiogenic phenotype .

Why and by what means some of the tumor cells leave the Tumor Dormancy and become angiogenic is not fully understood. The angiogenic switch itself can be triggered by hypoxia (lack of oxygen in the tissue ), further mutations in the genome of the tumor cells or via the activation of oncogenes or the deactivation of tumor suppressor genes . Thereafter, angiogenesis-stimulating messenger substances are increasingly expressed, as a result of which new blood vessels grow into the tumor. This connects the tumor to the blood and lymphatic system and opens the way to exponential growth in size and ultimately to metastasis.

Medical history

The term Dormancy tumor was first coined in 1934 by the Australian pathologist Rupert Allan Willis (1898–1980) in his monograph Spread of tumors in the human body . He found that after a supposedly curative removal of the primary tumor, tumor metastases can form after a long latency period . Until the 1990s, it was believed that tumor cells persist in the G0 phase of the cell cycle and are then reactivated. This hypothesis could be refuted in animal experiments . The model of a balanced proliferation and apoptosis rate was also developed in 1995 from animal experiments.

The American physician and cell biologist Judah Folkman made significant contributions to the Dormancy tumor .

Individual evidence

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  3. ↑ T. Udagawa: Tumor dormancy of primary and secondary cancers. In: APMIS 116, 2008, pp. 615-628. PMID 18834406 (Review)
  4. ↑ a b c N. Almog: Molecular mechanisms underlying tumor dormancy. In: Cancer Lett 294, 2010, pp. 139-146. PMID 20363069
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  6. ↑ MA Gimbrone, SB Leapman, RS Cotran, J. Folkman: tumor dormancy in vivo by prevention of neovascularization. In: The Journal of experimental medicine. Volume 136, Number 2, August 1972, pp. 261-276, PMID 5043412 , PMC 2139203 (free full text).
  7. ^ S. Brem et al.: Prolonged tumor dormancy by prevention of neovascularization in the vitreous. In: Cancer Res 36, 1976, pp. 2807-2812. PMID 127719
  8. ↑ J. Folkman and R. Kalluri: Cancer without disease. In: Nature 427, 2004, p. 787. PMID 14985739
  9. ^ J. Folkman : Angiogenesis in cancer, vascular, rheumatoid and other disease. In: Nat Med 1, 1995, pp. 27-31. PMID 7584949 (Review)
  10. ↑ D. Hanahan and J. Folkman : Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. In: Cell 86, 1996, pp. 353-364. PMID 8756718 (Review)
  11. ^ GN Naumov et al.: A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype. In: J Natl Cancer Inst 98, 2006, pp. 316-325. PMID 16507828
  12. ^ J. Folkman : Tumor angiogenesis. In: The molecular basis of Cancer J. Mendelsohn et al. (Ed.), WB Saunders Company, Philadelphia, 1995, ISBN 0-7216-6483-0 , p. 206.
  13. ^ A b G. Bergers and LE Benjamin: Tumorigenesis and the angiogenic switch. In: Nature Rev Cancer 3, 2002, pp. 401-410. PMID 12778130 (Review)
  14. ↑ L. Moserle include: The angiogenic switch: implications in the regulation of tumor dormancy. In: Curr Mol Med 9, 2009, pp. 935-941. PMID 19925406 (Review)
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  16. ↑ J. Soltau: Evaluation of the effect of bisphosphonates on tumor angiogenesis and their significance in adjuvant tumor therapy Dissertation, Albert-Ludwigs-Universität Freiburg im Breisgau, 2005 pp. 7–8.
  17. ↑ B. Manemann: VEGF and Flt-1 as prognostic factors in neoadjuvantly treated, locally advanced non-small cell lung tumors. (PDF; 9.4 MB) Dissertation, Ruhr University Bochum, 2003 p. 13.
  18. ^ J. Folkman et al .: Induction of angiogenesis during the transition from hyperplasia to neoplasia. In: Nature 339, 1989, pp. 58-61. PMID 2469964 .
  19. ^ N. Weidner et al.: Tumor angiogenesis and metastasis - correlation in invasive breast carcinoma. In: New England Journal of Medicine 324, 1991, pp. 1-8. PMID 1701519 .
  20. ↑ C. Dunau: Clinical testing of the tolerability and effectiveness of cationic liposome formulations in patients with squamous cell carcinoma of the head and neck area. Dissertation, LMU Munich 2010.
  21. ^ Willis, Rupert Allan (1898-1980) Australian Dictionary of Biography, accessed July 29, 2010.
  22. ^ RA Willis: Spread of tumors in the human body. J. & A. Churchill, 1934.
  23. ↑ C. Murray: Tumor dormancy: not so sleepy after all. In: Nat Med 12, 1995, pp 117-118. PMID 7585003 .
  24. ↑ L. Holmgren et al: Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. In: Nat Med 1, 1995, pp. 149-153. PMID 7585012 .
  25. ↑ B. Partzsch: Identification and isolation of angiostatin from the urine in patients with prostate cancer. (PDF; 694 kB) Dissertation, Julius Maximilians University of Würzburg, 2004.

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