Page 77 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

56 PART I The Biology and Pathogenesis of Cancer

bone marrow). Recent insights gleaned from the CSC model may 3. Vousden KH: Cell transformation by human papillomaviruses.
provide further support for the hypothesis that metastatic cells are In Minsen AC, Neil JC, McCrae MA, editors: Viruses and cancer,
Cambridge, 1994, Cambridge University Press.
capable of residence in transient sites such as the bone marrow,
VetBooks.ir where they may rest in a dormant state before being recruited into 4. Campo MS, O’Neil BW, Barron RJ, et al.: Experimental reproduc-
tion of the papilloma-carcinoma complex of the alimentary canal
the metastatic cascade. The signals that induce these presumed
in cattle, Carcinogenesis 15:1597–1601, 1994.
small populations of cells to break dormancy and emerge into 5. Campo MS, Jarrett WF, Barron R, et al.: Association of bovine
gross metastases likely also involve TME interaction. 224,225 papillomavirus type 2 and bracken fern with bladder cancer in
cattle, Cancer Res 52:6898–6904, 1992.
Metastasis Biology: New Perspectives 6. Donner P, Greiser-Wilkie I, Moelling K: Nuclear localization and
DNA binding of the transforming gene product of avian myelocy-
Metastasis is a nearly universally grave development for can- tomatosis virus, Nature 296:262–266, 1982.
cer patients, irrespective of specific cancer histology. An emerg- 7. Reid SW, Smith KT, Jarrett WF: Detection, cloning and character-
ing hypothesis proposes the existence of unique settings during isation of papillomaviral DNA present in sarcoid tumours of Equus
the metastatic cascade when metastatic cells are vulnerable and asinus, Vet Rec 135:430–432, 1994.
stressed. Cellular adaptation to stress in these vulnerable cells is 8. Gaukroger JM, Bradley A, Chandrachud L, et al.: Interaction
the most defining feature of metastatic proclivity and could be between bovine papillomavirus type 4 and cocarcinogens in the
production of malignant tumours, J Gen Virol 74(Pt 10):2275–
a target for new cancer drug development. Conversely, prolifera- 2280, 1993.
tion, apoptosis, invasion, and migration are neither sufficient nor 9. Jarrett WF: Bovine papilloma viruses, Clin Dermatol 3:8–19, 1985.
necessary for metastatic success and therefore do not necessarily 10. Lancaster WD, Olson C, Meinke W: Bovine papillomavirus: pres-
represent ideal targets for metastatic therapy. ence of virus-specific DNA sequences in naturally occurring equine
Consistent with the vulnerable cell hypothesis is the concept of tumours, Proc Nat Acad Sci U S A 74:524–528, 1977.
primary tumor reseeding. Some studies suggest that metastatic 11. Bertoli C, Skotheim JM, de Bruin RAM: Control of cell cycle tran-
cells that leave the primary tumor likely distribute to all tissues scription during G1 and S phases, Nat Rev Mol Cell Biol 14:518–
in the body by hematogenous spread; however, survival of rare 528, 2013.
single metastatic cells at distant sites predicts the future develop- 12. Casem ML: Cell Cycle. In Casem ML, editor: Case studies in cell
biology, ed 1, Cambridge, 2016, MA: Academic Press, pp 299–326.
ment of gross metastases. Included in this list of metastatic sites 13. Romanel A, Jensen LJ, Cardelli L, et al.: Transcriptional regulation
is the microenvironment of the primary tumor, suggesting that is a major controller of cell cycle transition dynamics, PLOS One
local recurrence is also a product of distant metastasis. This tumor 7:e29716, 2012.
reseeding hypothesis also suggests a rationale to study the value of 14. Otto T, Sicinski P: Cell cycle proteins as promising targets in can-
increased “surgical dose” in patients with nonlocalized tumors as a cer therapy, Nat Rev Cancer 17:93–115, 2017.
means to improve long-term outcomes. Conversely, the fact that 15. Golias CH, Charalabopoulos A, Charalabopoulos: Cell prolifera-
the vast majority of metastatic cells in an organ will never survive tion and cell cycle control: a mini review, Int J Clin Prac 58:1134–
or become a clinical problem should have us asking about the defi- 1141, 2004.
nitions of a metastatic site and the value of surgical resection of tis- 16. Kong N, Fotouhi N, Wovkulich PM, et al.: Cell cycle inhibitors for
the treatment of cancer, Drugs Future 28:881–896, 2003.
sues that have microscopic evidence of metastasis but no clinically 17. Maréchal A, Zou L: DNA Damage Sensing by the ATM and ATR
appreciated disease (i.e., a firm, fixed, and effaced lymph node).
kinases, Cold Spring Harb Perspect Biol 5:a012716, 2013.
18. Kastenhuber ER, Lowe SW: Putting p53 in context, CELL
Summary and Future Directions 170:1062–1078, 2017.
19. Lane DP: P53: guardian of the genome, Nature 358:15–16, 1992.
This chapter has sought to simplify as far as possible the mecha- 20. Brady CA, Attardi LD: p53 at a glance, J Cell Sci 123:2527–2532,
nisms of carcinogenesis and metastasis. Clearly, genomic insta- 2010.
bility and an environment of chronic inflammation support and 21. Levine AJ: P53, the cellular gatekeeper for growth and division,
provide a basis for the acquisition of the eight fundamental cancer Cell 88:323–331, 1997.
characteristics. The identification of these pathways is providing 22. Joerger AC, Fersht AR: The p53 pathway: origins, inactivation in
excellent clues to the underlying mechanisms in cancer and the cancer, and emerging therapeutic approaches, Annu Rev Biochem
85:375–404, 2016.
identification of potential therapeutic targets. However, despite 23. Wu X, Bayle JH, Olson D, et al.: The p53-mdm2 autoregulatory
the ability to make small molecules or antibodies, which aim at loop, Genes Dev 7:1126–1132, 1993.
key targets in cancer survival, we are still a long way from a cure. 24. Haupt Y, Maya R, Kazaz A, et al.: Mdm2 promotes the rapid deg-
The reasons for this are many but include inherent tumor hetero- radation of p53, Nature 387:296–299, 1997.
geneity (in part supplied by the existence of tumor stem cells), 25. Abegglen LM, Caulin AF, Chan A, et al.: Potential mechanisms for
continual tumor evolution, and the immense and underestimated cancer resistance in elephants and comparative cellular response to
contribution of the tumor microenvironment. Unquestionably, DNA damage in humans, J Am Med Assoc 314:1850–1860, 2015.
multiple approaches will be required to maximize any possibility 26. Strasser A, Cory S, Adams JM: Deciphering the rules of pro-
of therapeutic benefit. grammed cell death to improve therapy of cancer and other dis-
eases, EMBO J 30:3667–3683, 2011.
27. Jones S, Zhang X, Parsons DW, et al.: Core signaling pathways in
References human pancreatic cancers revealed by global genomic analyses, Sci-
ence 321:1801–1806, 2008.
1. McCance KL, Roberts LK: Cellular biology. In McCance KL, 28. Parsons DW, Jones S, Zhang X, et al.: An integrated genomic anal-
Huether SE, editors: Pathophysiology: the biologic basis of disease in ysis of human glioblastoma multiforme, Science 321:1807–1812,
adults and children, ed 3, St. Louis, 1997, Mosby. 2008.
2. Wyke J: Viruses and cancer. In Franks LM, Teich NM, editors: The 29. McCance KL, Roberts LK: The biology of cancer. In McCance KL,
molecular and cellular biology of cancer, ed 3, Oxford, 1997, Oxford Huether SE, editors: Pathophysiology: the biological basis of disease in
University Press. adults and children, ed 3, St. Louis, 1997, Mosby.