© The Author 2007. Published by Oxford University Press.
CORRESPONDENCE |
Re: A Model of Human Tumor Dormancy: An Angiogenic Escape From the Nonangiogenic Phenotype
Affiliations of authors: Departments of Thoracic and Vascular Surgery (PSN, PVS) and Pathology (EVM), University Hospital, University of Antwerp, Antwerp, Belgium
Correspondence to: Peyman Sardari Nia, MD, Department of Thoracic and Vascular Surgery, University Hospital, University of Antwerp, Antwerp, Wilrijkstraat 10, B-2650 Edegem, Belgium (e-mail: peyman.sardari.nia{at}uza.be).
We have read with great interest the study published by Naumov et al. (1), which provided a novel model of human tumor dormancy. However, we have some concerns regarding their basic assumptions and conclusions.
First, the basic assumption in the study by Naumov et al. is that tumor growth beyond the size of 1–2 mm is completely dependent on the angiogenic switch. However, the hypothesis that solid tumor growth is completely dependent on angiogenesis (angiogenic switch), which has prevailed for many years, has recently been challenged with the observations of angiogenesis-independent growth (referred to in the literature as nonangiogenic tumor growth). Solid tumor growth beyond the diffusion-limited size of 1–2 mm without elicited angiogenesis and with co-option of native vasculature of host tissue has been reported with increasing frequency and has been described in non–small-cell lung cancer (NSCLC), lung metastases, liver metastases, skin metastases, and lymph node metastases (2–4). Nonangiogenic tumor growth is not an exception; its frequency varies from 16% to 96% depending on the organ and the primary tumor (2–4).
An essential prerequisite for nonangiogenic tumor growth appears to be the ability of the tumor to preserve the stromal architecture of the host tissue as well as the preexisting blood vessels. Indeed, in NSCLC, an alveolar nonangiogenic tumor growth has been described in which tumor cell nests fill the alveolar spaces without destruction of the lung parenchyma, co-opting the septal blood vessels (2). Subsequent studies also suggested that the alveolar growth pattern is nonangiogenic in that incorporated blood vessels had the same phenotypic characteristics of native alveolar blood vessels, and a three-dimensional reconstruction of the tumor confirmed the preservation of stromal architecture of the lung (5,6). We have shown that an alveolar growth pattern is associated with poor prognosis in NSCLC and that this growth pattern is indeed nonangiogenic, being characterized by a low endothelial cell proliferation fraction and a high tumor cell proliferation fraction (7).
These observations add weight to the contention that tumor growth requires adequate vascularization rather than always being dependent on angiogenesis. We therefore argue that nonangiogenic phenotype is a specific disease entity rather than a preangiogenic state.
Second, an important question regarding the study of Naumov et al. is whether the observed angiogenic switch in a nonangiogenic tumor cell line was independent of the methodology. The nonangiogenic cell lines used in the study were probably completely dependent on angiogenesis because these cell lines could not grow in vivo beyond 1 mm in diameter. Although these cell lines were angiogenesis dependent, they probably, at inoculation, lacked the ability to induce angiogenesis. Naumov et al. have shown that these nonangiogenic cell lines, even before they switched from dormancy to the angiogenic phenotype, had high proliferation rates and were therefore not quiescent. It is also clear from their results that an angiogenic switch occurred in only a minority of mice inoculated with nonangiogenic cell lines, and only after at least 130–238 days. Therefore, it is possible that a nonangiogenic cell line with a high proliferation fraction could, after a long observation period, create subclones with the angiogenic switch through subsequent mutations. If so, then the cell line before and after the angiogenic switch would not be genetically identical. This has to be clarified before this model can be used for further studies.
REFERENCES
(1) Naumov GN, Bender E, Zurakowski D, Kang SY, Sampson D, Flynn E, et al. (2006) A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype. J Natl Cancer Inst 98:316–25.
(2) Sardari Nia P, Colpaert C, Blyweert B, Kui B, Vermeulen P, Ferguson M, et al. (2004) Prognostic value of nonangiogenic and angiogenic growth patterns in non-small cell lung cancer. Br J Cancer 91:1293–300.[CrossRef][Web of Science][Medline]
(3) Stessels F, Van den Eynden G, Van der Auwera I, Salgado R, Van den Heuvel E, Harris A, et al. (2004) Breast adenocarcinoma liver metastases express a nonangiogenic growth pattern that conserves the stroma and lacks hypoxia and fibrin deposition. Br J Cancer 90:1429–36.[CrossRef][Web of Science][Medline]
(4) Colpaert CG, Vermeulen PB, Van Besst P, Soubry A, Goovaerts G, Dirix LY, et al. (2003) Cutaneous breast cancer deposits show distinct growth patterns with different degrees of angiogenesis, hypoxia and fibrin deposition. Histopathology 42:530–40.[CrossRef][Web of Science][Medline]
(5) Passalidou E, Trivella M, Singh N, Ferguson M, Hu J, Cesario A, et al. (2002) Vascular phenotype in angiogenic and nonangiogenic lung non-small cell carcinomas. Br J Cancer 86:244–9.[CrossRef][Web of Science][Medline]
(6) Adighibe O, Micklem K, Campo L, Ferguson M, Harris A, Pozos R, et al. (2006) Is angiogenesis a novel pathway for cancer progression? A study using 3-dimensional tumour reconstructions. Br J Cancer 94:1176–9.[CrossRef][Web of Science][Medline]
(7) Sardari Nia P, Colpaert C, Vermeulen P, Van Marck E, Van Schil P. (2005) A novel biologic classification of non-small cell lung cancer. Eur Respir J 26:Suppl 49, s182.[CrossRef]
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J Natl Cancer Inst 2007 99: 331-332.
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