A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype
Open accessAbstract
BACKGROUND: Microscopic human cancers can remain dormant for life. Tumor progression depends on sequential events, including a switch to the angiogenic phenotype, i.e., initial recruitment of new vessels. We previously demonstrated that human tumors contain tumor cell populations that are heterogeneous in angiogenic activity. Here, we separated angiogenic from nonangiogenic human tumor cell populations and compared their growth. METHODS: Severe combined immunodeficient (SCID) mice were inoculated with nonangiogenic human MDA-MB-436 breast adenocarcinoma, KHOS-24OS osteosarcoma, or T98G glioblastoma cells. Most of the resulting tumors remained microscopic (<1 mm diameter), but some eventually became angiogenic and enlarged and were used to isolate angiogenic tumor cells. Angiogenic and nonangiogenic tumor cells were inoculated into SCID mice, and time to the development of palpable tumors was determined. Cell proliferation was assayed in vitro by growth curves and in vivo by staining for proliferating cell nuclear antigen or Ki67. Microscopic tumors from both tumor cell populations were examined for histologic evidence of vascular development 14 days after inoculation in mice. Expression of the angiogenesis inhibitor thrombospondin-1 was examined by immunoblotting. RESULTS: Nonangiogenic tumors of each tumor type developed palpable tumors after means of 119 days (range: 53-185 days) for breast cancer, 238 days (184-291 days) for osteosarcoma, and 226 days (150-301 days) for glioblastoma. Angiogenic cells developed palpable tumors within 20 days after inoculation. However, nonangiogenic and angiogenic cells of each tumor type had similar proliferation rates. Fourteen days after tumor cell inoculation, tumors from angiogenic cells showed evidence of functional vasculature. In contrast, nonangiogenic tumors remained microscopic in size with absent or nonfunctional vasculature. Thrombospondin-1 expression was statistically significantly lower (by five- to 23-fold, depending on tumor type) in angiogenic than nonangiogenic cells. CONCLUSIONS: This model provides a conceptual framework and a reproducible in vivo system to study unresolved central questions in cancer biology regarding the initiation, reversibility, and molecular regulation of the timing of the angiogenic switch.
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The authors' in vivo mouse model showed tumor growth kinetics and incidence similar to dormant cancer cell line models, unlike studies using aggressive cancer cell lines that often produce tumors larger than 100 mm3 within a month after implantation.
“Importantly, our in vivo mouse model displayed tumor growth kinetics and incidence similar to dormant cancer cell line models [93–96], in contrast to studies relying on aggressive cancer cell lines and resulting often into >100mm3 tumors less than a month after implantation [7].”
From Mesenchymal stem cell secretome and regenerative therapy after cancer (2013) · cites this paper as [93]
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- Authors
- Naumov, G. N., Bender, E., Zurakowski, D., Kang, S.-Y., Sampson, D., Flynn, E., Watnick, R. S., Straume, O., Akslen, L. A., Folkman, J., & Almog, N.
- Affiliations
- Harvard University (US)
- Corresponding author
- Naumov, George N.
- Venue
- JNCI: Journal of the National Cancer Institute
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-03-01
- Volume
- 98
- Issue
- 5
- Pages
- 316-325
- ISSN
- 0027-8874 (ISSN-L)
- 1460-2105
- OpenAlex
- W2136379419
- Cited by
- 423
- References
- 35
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 9 · 2023: 11 · 2022: 14 · 2021: 12 · 2020: 13 · 2019: 15 · 2018: 20 · 2017: 23 · 2016: 12 · 2015: 21 · 2014: 20 · 2013: 28 · 2012: 36
- FWCI
- 15.51
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- JNCI Journal of the National Cancer Institute (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Physical Sciences › Mathematics › Modeling and Simulation › Mathematical Biology Tumor Growth
- Keywords
- tumor dormancy, angiogenic switch, tumor angiogenesis, tumor heterogeneity, thrombospondin-1, tumor cell proliferation, tumor vasculature, breast adenocarcinoma, osteosarcoma, glioblastoma, tumor growth kinetics
- MeSH terms
- Adenocarcinoma, Animals, Enzyme-Linked Immunosorbent Assay, Glioblastoma, Humans, Immunohistochemistry, Neovascularization, Pathologic, Phenotype, Osteosarcoma, Time Factors, Tumor Cells, Cultured, Immunoblotting, Gene Expression Regulation, Neoplastic, Fibroblast Growth Factor 2, Mice, SCID, Thrombospondin 1, In Situ Nick-End Labeling, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Cell Proliferation, Mice
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