© The Author 2007. Published by Oxford University Press.
CORRESPONDENCE |
Response: Re: A Model of Human Tumor Dormancy: An Angiogenic Escape From the Nonangiogenic Phenotype
Affiliation of authors: Department of Surgery, Vascular Biology Program, Children's Hospital and Harvard Medical School, Boston, MA (GNN, RSW, NA, JF); The Gade Institute, Section for Pathology, University of Bergen, Norway (LAA)
Correspondence to: Judah Folkman, MD, Karp Family Research Laboratories 12.128, 300 Longwood Ave, Boston, MA 02115 (e-mail: judah.folkman{at}childrens.harvard.edu).
We appreciate the comments of Sardari Nia et al. It is well established in the literature that all expanding tumors need a supporting vasculature. Sardari Nia et al. contend that large tumors can grow by co-option, a process that was first described by Holash et al. (1), who demonstrated that tumor cells can grow as perivascular cuffs in thickness no more than the oxygen diffusion limit. The oxygen diffusion limit has been defined previously as 200–250 µm or less (2,3). Beyond this tumor thickness, virtually all published studies reveal the requirement for neovascularization, i.e., new vessel sprouts, a hallmark of the angiogenic process (4). In contrast, the co-option process has not been shown to be dependent on vascular sprouting or to be capable of supporting tumor growth beyond 1–2 mm in diameter.
In some instances, tumor growth by co-option may follow the stromal architecture of the host tissue, as exemplified by Sardari Nia et al. Such tumors would be appropriately called "nonangiogenic" because no new vascular sprouting was observed. It appears that the authors’ main criticism of our study is with our use of the term "nonangiogenic" to describe one form of the dormant tumor phenotype. This use of the term apparently conflicts with their use of the term, to describe tumors that do not appear to require angiogenesis for continued increase in mass. However, we stated clearly at the outset of our article that blocked angiogenesis (i.e., absence of angiogenesis) is not the only mechanism of tumor dormancy. For example, hormone deprivation or immune responses can also induce tumor dormancy. We are puzzled about how the semantic argument by Sardari Nia et al. bears on the results we describe or the conclusions we draw from them.
It is possible that co-option of the tumor vascular supply may play a role in the maintenance of microscopic tumors (1), but we know of no strong evidence that macroscopic tumors with increasing mass can grow by co-option alone. The proof of co-option as a method of permitting large mass of tumor growth without new vascular sprouts would require careful confocal microscopy coupled with the use of an intravascular dye, such as lectin (5). Turner et al. (6) emphasized that tumor angiogenesis can also be measured in vivo by magnetic resonance imaging using a contrast agent targeted to the 
V
3 integrin, which is more strongly expressed on angiogenic than on normal blood vessels. Alternatively, using histologic methods, it is practical to use an antibody (e.g., LH39) that recognizes an epitope found only in mature vessels and to compare the presence of this epitope with vascular counts using CD31, which recognizes both mature and newly formed vessels. This latter approach allows a measurement of active vascular remodeling, rather than a static vessel count (6).
Whereas angiogenesis, by definition, requires new microvascular sprouts (4,5), these sprouts can grow by endothelial migration even in the absence of endothelial cell proliferation (7). Therefore, we do not feel that co-option and angiogenesis are mutually exclusive. They may, in fact, coexist in the same tumor.
Sardari Nia et al. also suggest that the switch to an angiogenic phenotype by the tumor cells we used could be mediated by genetic mutations occurring during the period (months) of nonangiogenic existence in vivo. In our study, we did not assert that tumor cells emerging from an angiogenic switch are genetically identical to those that existed before the switch. On the contrary, multiple genetic and epigenetic events are likely to occur during the acquisition of an angiogenic phenotype as tumor growth proceeds. For example, in our paper, we demonstrated an increased expression of the Myc oncogene in angiogenic tumor cells compared to nonangiogenic tumor cells.
In summary, it is not uncommon in a rapidly developing new field, such as angiogenesis research, for conflicting interpretations to arise and for disagreements to emerge because discoveries can outpace methodology.
REFERENCES
(1) Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, et al. (1999) Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284:1994–8.
(2) Tannock IF. (1968) The relation between cell proliferation and the vascular system in a transplanted mouse mammary tumour. Br J Cancer 22:258–73.[Medline]
(3) Torres Filho IP, Lenning M, Yuan F, Intaglietta M, Jain RK. (1994) Noninvasive measurement of microvascular and interstitial oxygen profiles in a human tumor in SCID mice. Proc Natl Acad Sci U S A 91:2081–5.
(4) Folkman J. (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–6.[ISI][Medline]
(5) Mancuso MR, Davis R, Norberg SM, O’Brien S, Sennino B, Nakahara T, et al. (2006) Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest 116:2610–21.[CrossRef][ISI][Medline]
(6) Turner HE, Harris AL, Melmed S, Wass JA. (2003) Angiogenesis in endocrine tumors. Endocr Rev 24:600–32.
(7) Sholley MM, Ferguson GP, Seibel HR, Montour JL, Wilson JD. (1984) Mechanisms of neovascularization: vascular sprouting can occur without proliferation of endothelial cells. Lab Invest 51:624–34.[ISI][Medline]
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J Natl Cancer Inst 2007 99: 331.
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