| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Regular Articles |
From the Molecular and Cellular Biology Research
Program,*
Sunnybrook and Women’s College Health Sciences
Centre, Toronto, Ontario, Canada; the Department of Medical
Biophysics,
University of Toronto, Toronto,
Ontario, Canada; the Hamilton Civic Hospitals Research
Centre,
McMaster University, Hamilton,
Ontario, Canada; the Samuel Lunenfeld Research
Institute,¶
Mt. Sinai Hospital, Toronto, Ontario,
Canada; the Department of Biomedical Sciences,||
Ontario
Veterinary College, University of Guelph, Guelph, Ontario, Canada; and
The Centre for Transgene Technology and Gene
Therapy,§
Flanders Interuniversity Institute
for Biotechnology, Leuven, Belgium
Cells within a tumor are highly heterogeneous with respect to a
wide range of genotypic and phenotypic characteristics. The latter
include such properties as growth, survival,
invasion, and metastasis. We asked whether the degree to which
individual tumor cells rely on a tumor’s vasculature might also be
heterogeneous. By adapting an intravital Hoechst 33342 staining
technique, we labeled and isolated tumor cells based on their
relative proximity to perfused vessels. Because tumor regions distal to
the vasculature are likely hypoxic, we examined cells deficient
for hypoxia-inducible factor-1
(HIF-1), a transcription
factor that has been shown to mediate hypoxia-induced
responses, including apoptosis. Despite reduced vascularization
in HIF-1-/- embryonic stem cell-derived
tumors, their growth in vivo was found to be
accelerated relative to HIF-1+/+ tumor counterparts. We
hypothesized that this paradoxical observation is because of decreased
apoptotic rate, resulting in diminished vascular dependence of
HIF-1-/- cells. Analysis of heterogeneous tumors
established from mixtures of HIF-1+/+ with
HIF-1-/- cells revealed that the proportion of cells
expressing wild-type HIF-1 was increased in perivascular areas and
decreased in distal tumor regions. Thus, cells expressing
HIF-1 were found to be highly dependent on proximity to blood
vessels for their growth and survival in vivo,
whereas cells that had lost HIF-1 expression were much less so.
Heterogeneity in angiogenesis dependence was also observed among cell
subpopulations isolated from human melanoma xenografts. This potential
for selection of less vascular-dependent tumor cell variants throughout
the course of disease progression may have important implications for
the long-term efficacy of anti-angiogenic therapy.
This article has been cited by other articles:
 |
|
 |
|
  J. Yu, L. May, C. Milsom, G. M. Anderson, J. I. Weitz, J. P. Luyendyk, G. Broze, N. Mackman, and J. Rak Contribution of Host-Derived Tissue Factor to Tumor Neovascularization Arterioscler. Thromb. Vasc. Biol., November 1, 2008; 28(11): 1975 - 1981. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Krneta, J. Kroll, F. Alves, C. Prahst, F. Sananbenesi, C. Dullin, S. Kimmina, D. J. Phillips, and H. G. Augustin Dissociation of Angiogenesis and Tumorigenesis in Follistatin- and Activin-Expressing Tumors Cancer Res., June 1, 2006; 66(11): 5686 - 5695. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Roberts, B. Kloos, M. Cassella, S. Podgrabinska, K. Persaud, Y. Wu, B. Pytowski, and M. Skobe Inhibition of VEGFR-3 Activation with the Antagonistic Antibody More Potently Suppresses Lymph Node and Distant Metastases than Inactivation of VEGFR-2. Cancer Res., March 1, 2006; 66(5): 2650 - 2657. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. E. Fathers, C. M. Stone, K. Minhas, J. J.A. Marriott, J. D. Greenwood, D. J. Dumont, and B. L. Coomber Heterogeneity of Tie2 Expression in Tumor Microcirculation: Influence of Cancer Type, Implantation Site, and Response to Therapy Am. J. Pathol., December 1, 2005; 167(6): 1753 - 1762. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Shahrzad, L. Quayle, C. Stone, C. Plumb, S. Shirasawa, J. W. Rak, and B. L. Coomber Ischemia-Induced K-ras Mutations in Human Colorectal Cancer Cells: Role of Microenvironmental Regulation of MSH2 Expression Cancer Res., September 15, 2005; 65(18): 8134 - 8141. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sobhanifar, C. Aquino-Parsons, E. J. Stanbridge, and P. Olive Reduced Expression of Hypoxia-Inducible Factor-1{alpha} in Perinecrotic Regions of Solid Tumors Cancer Res., August 15, 2005; 65(16): 7259 - 7266. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Gasparini, R. Longo, M. Fanelli, and B. A. Teicher Combination of Antiangiogenic Therapy With Other Anticancer Therapies: Results, Challenges, and Open Questions J. Clin. Oncol., February 20, 2005; 23(6): 1295 - 1311. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Bello, V. Lucini, F. Costa, M. Pluderi, C. Giussani, F. Acerbi, G. Carrabba, M. Pannacci, D. Caronzolo, S. Grosso, et al. Combinatorial Administration of Molecules That Simultaneously Inhibit Angiogenesis and Invasion Leads to Increased Therapeutic Efficacy in Mouse Models of Malignant Glioma Clin. Cancer Res., July 1, 2004; 10(13): 4527 - 4537. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Arsham, D. R. Plas, C. B. Thompson, and M. C. Simon Akt and Hypoxia-Inducible Factor-1 Independently Enhance Tumor Growth and Angiogenesis Cancer Res., May 15, 2004; 64(10): 3500 - 3507. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Hopfl, O. Ogunshola, and M. Gassmann HIFs and tumors--causes and consequences Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2004; 286(4): R608 - R623. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. G. Eccles, A. Patel, A. Verma, D. Nicholson, Y. Lukes, R. M. Tuttle, and G. L. Francis Erythropoietin and the Erythropoietin Receptor Are Expressed by Papillary Thyroid Carcinoma fromChildren and Adolescents.: Expression of Erythropoietin Receptor Might Be a Favorable Prognostic Indicator Ann. Clin. Lab. Sci., October 1, 2003; 33(4): 411 - 422. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. R. White, S. Shan, C. P. Rusconi, G. Shetty, M. W. Dewhirst, C. D. Kontos, and B. A. Sullenger Inhibition of rat corneal angiogenesis by a nuclease-resistant RNA aptamer specific for angiopoietin-2 PNAS, April 29, 2003; 100(9): 5028 - 5033. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. D. Miller, C. J. Sweeney, and G. W. Sledge The Snark is a Boojum: the continuing problem of drug resistance in the antiangiogenic era Ann. Onc., January 1, 2003; 14(1): 20 - 28. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Gee, W. N. Procopio, S. Makonnen, M. D. Feldman, N. M. Yeilding, and W. M. F. Lee Tumor Vessel Development and Maturation Impose Limits on the Effectiveness of Anti-Vascular Therapy Am. J. Pathol., January 1, 2003; 162(1): 183 - 193. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Hammond, A. J. Giaccia, T. Browder, J. Folkman, P. Hahnfeldt, J. Heymach, L. Hlatky, M. Kieran, M. S. Rogers, Robert. S. Kerbel, et al. Antiangiogenic Therapy and p53 Science, July 26, 2002; 297(5581): 471a - 471. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. J. P. Beasley, R. Leek, M. Alam, H. Turley, G. J. Cox, K. Gatter, P. Millard, S. Fuggle, and A. L. Harris Hypoxia-inducible Factors HIF-1{alpha} and HIF-2{alpha} in Head and Neck Cancer: Relationship to Tumor Biology and Treatment Outcome in Surgically Resected Patients Cancer Res., May 1, 2002; 62(9): 2493 - 2497. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Hopfl, R. H. Wenger, U. Ziegler, T. Stallmach, O. Gardelle, R. Achermann, M. Wergin, B. Kaser-Hotz, H. M. Saunders, K. J. Williams, et al. Rescue of Hypoxia-inducible Factor-1{alpha}-deficient Tumor Growth by Wild-Type Cells Is Independent of Vascular Endothelial Growth Factor Cancer Res., May 1, 2002; 62(10): 2962 - 2970. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Rak, J. L. Yu, R. S. Kerbel, and B. L. Coomber What Do Oncogenic Mutations Have To Do with Angiogenesis/Vascular Dependence of Tumors? Cancer Res., April 1, 2002; 62(7): 1931 - 1934. [Full Text] [PDF]
|
|
|
|
|
|
J. L. Yu, J. W. Rak, G. Klement, and R. S. Kerbel Vascular Endothelial Growth Factor Isoform Expression as a Determinant of Blood Vessel Patterning in Human Melanoma Xenografts Cancer Res., March 1, 2002; 62(6): 1838 - 1846. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Yu, J. W. Rak, B. L. Coomber, D. J. Hicklin, and R. S. Kerbel Effect of p53 Status on Tumor Response to Antiangiogenic Therapy Science, February 22, 2002; 295(5559): 1526 - 1528. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Lee, D. C. Kim, M. S. Gee, H. M. Saunders, C. M. Sehgal, M. D. Feldman, S. R. Ross, and W. M. F. Lee Interleukin-12 Inhibits Angiogenesis and Growth of Transplanted but not in Situ Mouse Mammary Tumor Virus-induced Mammary Carcinomas Cancer Res., February 1, 2002; 62(3): 747 - 755. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Kerbel Clinical Trials of Antiangiogenic Drugs: Opportunities, Problems, and Assessment of Initial Results J. Clin. Oncol., September 15, 2001; 19(90001): 45s - 51. [Full Text] [PDF]
|
|
|
|
|
|
D. Fukumura, L. Xu, Y. Chen, T. Gohongi, B. Seed, and R. K. Jain Hypoxia and Acidosis Independently Up-Regulate Vascular Endothelial Growth Factor Transcription in Brain Tumors in Vivo Cancer Res., August 1, 2001; 61(16): 6020 - 6024. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
