Abstract
An increasingly appreciated focus of carcinogenesis research is on mechanisms governing tumor growth after the fact of cancer cell creation. Of particular interest are dynamical interactions between tumor and host cell populations that can themselves strongly impact the fate of established cancer lesions. Regardless of tumor type, all cancers face the common problem of having to breach the barrier of angiogenic competency in order to advance from a microscopic lesion to symptomatic disease. If pre-angiogenic tumor cells are held in dormancy due to cell cycle arrest, this will postpone the need to traverse this higher-level barrier. On the other hand, the barrier itself may prove limiting to a tumor at its diffusion-limited size, creating a population-level dormancy characterized by balanced proliferation and cell death. In both cases of dormancy, the “angiogenic switch” has not yet occurred. We here describe and mathematically quantify an underappreciated third dormancy state defined by an angiogenic balance following the angiogenic switch. In this state we term “post-vascular dormancy,” a tumor has attained angiogenic competency, but again demonstrates balanced proliferation and cell death because ambient pro- and anti-angiogenic influences are offsetting. Interestingly, autopsies have shown virtually all of us carry latent tumors in pre- or post-vascular states, many of which lie under the threshold of routine clinical detection. We show how, in the post-vascular case, tumor latency can arise from an elaborate mechanism of self-controlled growth, mediated through the tumor–vascular interaction. Underlying this observation is the finding that a tumor produces both angiogenesis stimulators and inhibitors, with the latter having greater influence, both locally and systemically, as the tumor grows—a mechanism we hypothesize is an aberrant co-option of normal organogenic regulation. That a tumor can limit its own growth raises the prospect that chronic therapies aimed at suppressing this tumor–host dynamic may compare favorably to current strategies which often yield favorable short-term responses but fail to deliver long-term tumor suppression.
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References
Cheng L, Bostwick DG, Li G, Wang Q, Hu N, Vortmeyer AO, Zhuang Z (1999) Allelic imbalance in the clonal evolution of prostate carcinoma. Cancer 85(9):2017–2022
Stilgenbauer S, Sander S, Bullinger L, Benner A, Leupolt E, Winkler D, Kröber A, Kienle D, Lichter P, Döhner H (2007) Clonal evolution in chronic lymphocytic leukemia: acquisition of high-risk genomic aberrations associated with unmutated VH, resistance to therapy, and short survival. Haematologica 92(9):1242–1245
Losi L, Baisse B, Bouzourene H, Benhattar J (2005) Evolution of intratumoral genetic heterogeneity during colorectal cancer progression. Carcinogenesis 26(5):916–922
Illmensee K, Mintz B (1976) Totipotency and normal differentiation of single teratocarcinoma cells cloned by injection into blastocysts. Proc Natl Acad Sci USA 73(2):549–553
Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S, Washington MK, Neilson EG, Moses HL (2004) TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303(5659):848–851
Bissell MJ, Radisky D (2001) Putting tumours in context. Nat Rev Cancer 1(1):46–54
Nguyen DH, Oketch-Rabah HA, Illa-Bochaca I, Geyer FC, Reis-Filho JS, Mao JH, Ravani SA, Zavadil J, Borowsky AD, Jerry DJ, Dunphy KA, Seo JH, Haslam S, Medina D, Barcellos-Hoff MH (2011) Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type. Cancer Cell 19(5):640–651
Black WC, Welch HG (1993) Advances in diagnostic imaging and overestimations of disease prevalence and the benefits of therapy. N Engl J Med 328(17):1237–1243
Welch HG, Black WC (2010) Overdiagnosis in cancer. J Natl Cancer Inst 102(9):605–613
Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3(6):401–410
Davis DW, Herbst RS, Abbruzzese JL (eds) (2007) Antiangiogenic cancer therapy. Boca Raton, CRC
Cao Y, O’Reilly MS, Marshall B, Flynn E, Ji RW, Folkman J (1998) Expression of angiostatin cDNA in a murine fibrosarcoma suppresses primary tumor growth and produces long-term dormancy of metastases. J Clin Invest 101(5):1055–1063
Udagawa T, Fernandez A, Achilles EG, Folkman J, D’Amato RJ (2002) Persistence of microscopic human cancers in mice: alterations in the angiogenic balance accompanies loss of tumor dormancy. FASEB J 16(11):1361–1370
Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438(7069):820–827
O’Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J (1994) Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79(2):315–328
O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88(2):277–285
Hahnfeldt P, Panigrahy D, Folkman J, Hlatky L (1999) Tumor development under angiogenic signaling: a dynamical theory of tumor growth, treatment response, and postvascular dormancy. Cancer Res 59(19):4770–4775
Willis RA (1948) Pathology of Tumours. Butterworth, London
Hadfield G (1954) The dormant cancer cell. Br Med J 2(4888):607–610
Guba M, Cernaianu G, Koehl G, Geissler EK, Jauch KW, Anthuber M, Falk W, Steinbauer M (2001) A primary tumor promotes dormancy of solitary tumor cells before inhibiting angiogenesis. Cancer Res 61(14):5575–5579
Wheelock EF, Weinhold KJ, Levich J (1981) The tumor dormant state. Adv Cancer Res 34:107–140
Meltzer A (1990) Dormancy and breast cancer. J Surg Oncol 43(3):181–188
Fontana RS, Sanderson DR, Woolner LB, Taylor WF, Miller WE, Muhm JR, Bernatz PE, Payne WS, Pairolero PC, Bergstralh EJ (1991) Screening for lung cancer. A critique of the Mayo Lung Project. Cancer 67(4 suppl):1155–1164
Marcus PM, Bergstralh EJ, Zweig MH, Harris A, Offord KP, Fontana RS (2006) Extended lung cancer incidence follow-up in the Mayo Lung Project and overdiagnosis. J Natl Cancer Inst 98(11):748–756
Nielsen M, Thomsen JL, Primdahl S, Dyreborg U, Andersen JA (1987) Breast cancer and atypia among young and middle-aged women: a study of 110 medicolegal autopsies. Br J Cancer 56(6):814–819
Almog N, Henke V, Flores L, Hlatky L, Kung AL, Wright RD, Berger R, Hutchinson L, Naumov GN, Bender E, Akslen LA, Achilles EG, Folkman J (2006) Prolonged dormancy of human liposarcoma is associated with impaired tumor angiogenesis. FASEB J 20(7):947–949
Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86(3):353–364
Abdollahi A, Schwager C, Kleeff J, Esposito I, Domhan S, Peschke P, Hauser K, Hahnfeldt P, Hlatky L, Debus J, Peters JM, Friess H, Folkman J, Huber PE (2007) Transcriptional network governing the angiogenic switch in human pancreatic cancer. Proc Natl Acad Sci USA 104(31):12890–12895
Indraccolo S, Favaro E, Amadori A (2006) Dormant tumors awaken by a short-term angiogenic burst: the spike hypothesis. Cell Cycle 5(16):1751–1755
Coffey JC, Wang JH, Smith MJ, Boucher-Hayes D, Cotter TG, Redmond HP (2003) Excisional surgery for cancer cure: therapy at a cost. Lancet Oncol 4(12):760–768
Baum M, Demicheli R, Hrushesky W, Retsky M (2005) Does surgery unfavourably perturb the “natural history” of early breast cancer by accelerating the appearance of distant metastases? Eur J Cancer 41(4):508–515
von Fournier D, Weber E, Hoeffken W, Bauer M, Kubli F, Barth V (1980) Growth rate of 147 mammary carcinomas. Cancer 45(8):2198–2207
Abdollahi A, Folkman J (2010) Evading tumor evasion: current concepts and perspectives of anti-angiogenic cancer therapy. Drug Resist Updat 13(1–2):16–28
Rastinejad F, Polverini PJ, Bouck NP (1989) Regulation of the activity of a new inhibitor of angiogenesis by a cancer suppressor gene. Cell 56(3):345–355
Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2(10):727–739
Tsoularis A (2001) Analysis of logistic growth models. Res Lett Inf Math Sci 2:23–46
Spratt JS, Meyer JS, Spratt JA (1996) Rates of growth of human neoplasms: Part II. J Surg Oncol 61(1):68–83
Zetter BR (1998) Angiogenesis and tumor metastasis. Annu Rev Med 49:407–424
Ribatti D (2008) Judah Folkman, a pioneer in the study of angiogenesis. Angiogenesis 11(1):3–10
Figg WD, Pluda JM, Lush RM, Saville MW, Wyvill K, Reed E, Yarchoan R (1997) The pharmacokinetics of TNP-470, a new angiogenesis inhibitor. Pharmacotherapy 17(1):91–97
Peeters CF, Westphal JR, de Waal RM, Ruiter DJ, Wobbes T, Ruers TJ (2004) Vascular density in colorectal liver metastases increases after removal of the primary tumor in human cancer patients. Int J Cancer 112(4):554–559
van der Bij GJ, Oosterling SJ, Beelen RH, Meijer S, Coffey JC, van Egmond M (2009) The perioperative period is an underutilized window of therapeutic opportunity in patients with colorectal cancer. Ann Surg 249(5):727–734
Lammert E, Cleaver O, Melton D (2003) Role of endothelial cells in early pancreas and liver development. Mech Dev 120(1):59–64
Yoshitomi H, Zaret KS (2004) Endothelial cell interactions initiate dorsal pancreas development by selectively inducing the transcription factor Ptf1a. Development 131(4):807–817
Greene AK, Wiener S, Puder M, Yoshida A, Shi B, Perez-Atayde AR, Efstathiou JA, Holmgren L, Adamis AP, Rupnick M, Folkman J, O’Reilly MS (2003) Endothelial-directed hepatic regeneration after partial hepatectomy. Ann Surg 237(4):530–535
Acknowledgments
This project was supported by the National Cancer Institute under Award Number U54CA149233 (to L. Hlatky). The content is solely the responsibility of the author and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. Figure 2.5 graphics due to Clare Lamont.
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Hahnfeldt, P. (2013). The Host Support Niche as a Control Point for Tumor Dormancy: Implications for Tumor Development and Beyond. In: Enderling, H., Almog, N., Hlatky, L. (eds) Systems Biology of Tumor Dormancy. Advances in Experimental Medicine and Biology, vol 734. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-1445-2_2
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DOI: https://doi.org/10.1007/978-1-4614-1445-2_2
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