• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of amjpatholAmerican Journal of Pathology For AuthorsAmerican Journal of Pathology SubscribeAmerican Journal of Pathology SearchAmerican Journal of Pathology Current IssueAmerican Journal of Pathology About the JournalAmerican Journal of Pathology
Am J Pathol. Jun 1998; 152(6): 1607–1616.
PMCID: PMC1858460

Impact of fibroblast growth factor-2 on tumor microvascular architecture. A tridimensional morphometric study.


Three cell clones originated by transfection of human endometrial adenocarcinoma HEC-1-B cells with fibroblast growth factor-2 (FGF-2) cDNA and characterized by a different capacity to produce and secrete the growth factor were transplanted subcutaneously in nude mice. Corrosion casting of the tumor microvasculature of xenografts produced by injection of 2 x 10(6) or 10 x 10(6) FGF-2-B9 cells (which produce and secrete significant amounts of FGF-2), 10 x 10(6) FGF-2-A8 cells (which produce comparable amounts of FGF-2 but do not secrete it), or 10 x 10(6) control FGF-2-B8 cells (which produce only trace amounts of FGF-2) was performed after 14 days of growth. Interbranching distances, intervascular distances, branching angles, and vessel diameters were then determined using tridimensional stereo pairs of the casted tumor vascularity. When transplanted at the same concentration, FGF-2-B9 cells grew faster in nude mice compared with FGF-2-A8 and FGF-2-B8 clones. The total amount of new vessel formation was far higher in FGF-2-B9 tumors than in FGF-2-B8 or FGF-2-A8 tumors. Also, vessel courses were more irregular and blind-ending vessels and evasates were more frequent in FGF-2-B9 tumors. Moreover, FGF-2-B9 tumor microvasculature was characterized by a wider average vascular diameter and by an extreme variability of the diameter of each individual vessel along its course between two ramifications. No statistical differences were observed when the distribution curves of the values of intervascular distances, interbranching distances, and branching angles of the microvessel network were compared among the different experimental groups. The distinctive features of the microvasculature of FGF-2-B9 tumors were retained, at least in part, in the smaller lesions produced by injection of a limited number of cells. The data indicate that FGF-2 production and release confer to FGF-2-B9 cells the ability to stimulate the formation of new blood vessels with distinctive architectural features. Neovascularization of FGF-2-B9 lesions parallels the faster rate of growth of the neoplastic parenchyma. This does not affect the overall architecture of the microvessel network that appears to be primed by characteristics of the HEC-1-B tumor cell line and/or by the microenvironment of the host. To our knowledge, this work represents the first attempt to define the influence of a single, defined growth factor on the tridimensional tumor vascular pattern.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.2M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996 Aug 9;86(3):353–364. [PubMed]
  • Konerding MA, Miodonski AJ, Lametschwandtner A. Microvascular corrosion casting in the study of tumor vascularity: a review. Scanning Microsc. 1995;9(4):1233–1244. [PubMed]
  • Dellian M, Witwer BP, Salehi HA, Yuan F, Jain RK. Quantitation and physiological characterization of angiogenic vessels in mice: effect of basic fibroblast growth factor, vascular endothelial growth factor/vascular permeability factor, and host microenvironment. Am J Pathol. 1996 Jul;149(1):59–71. [PMC free article] [PubMed]
  • Burgess WH, Maciag T. The heparin-binding (fibroblast) growth factor family of proteins. Annu Rev Biochem. 1989;58:575–606. [PubMed]
  • Baird A, Klagsbrun M. The fibroblast growth factor family. Cancer Cells. 1991 Jun;3(6):239–243. [PubMed]
  • Gospodarowicz D. Biological activities of fibroblast growth factors. Ann N Y Acad Sci. 1991;638:1–8. [PubMed]
  • Folkman J, Klagsbrun M. Angiogenic factors. Science. 1987 Jan 23;235(4787):442–447. [PubMed]
  • Presta M, Moscatelli D, Joseph-Silverstein J, Rifkin DB. Purification from a human hepatoma cell line of a basic fibroblast growth factor-like molecule that stimulates capillary endothelial cell plasminogen activator production, DNA synthesis, and migration. Mol Cell Biol. 1986 Nov;6(11):4060–4066. [PMC free article] [PubMed]
  • Moscatelli D, Presta M, Joseph-Silverstein J, Rifkin DB. Both normal and tumor cells produce basic fibroblast growth factor. J Cell Physiol. 1986 Nov;129(2):273–276. [PubMed]
  • Halaban R, Kwon BS, Ghosh S, Delli Bovi P, Baird A. bFGF as an autocrine growth factor for human melanomas. Oncogene Res. 1988 Sep;3(2):177–186. [PubMed]
  • Okumura N, Takimoto K, Okada M, Nakagawa H. C6 glioma cells produce basic fibroblast growth factor that can stimulate their own proliferation. J Biochem. 1989 Nov;106(5):904–909. [PubMed]
  • Nakamoto T, Chang CS, Li AK, Chodak GW. Basic fibroblast growth factor in human prostate cancer cells. Cancer Res. 1992 Feb 1;52(3):571–577. [PubMed]
  • Schulze-Osthoff K, Risau W, Vollmer E, Sorg C. In situ detection of basic fibroblast growth factor by highly specific antibodies. Am J Pathol. 1990 Jul;137(1):85–92. [PMC free article] [PubMed]
  • Zagzag D, Miller DC, Sato Y, Rifkin DB, Burstein DE. Immunohistochemical localization of basic fibroblast growth factor in astrocytomas. Cancer Res. 1990 Nov 15;50(22):7393–7398. [PubMed]
  • Ohtani H, Nakamura S, Watanabe Y, Mizoi T, Saku T, Nagura H. Immunocytochemical localization of basic fibroblast growth factor in carcinomas and inflammatory lesions of the human digestive tract. Lab Invest. 1993 May;68(5):520–527. [PubMed]
  • Takahashi JA, Mori H, Fukumoto M, Igarashi K, Jaye M, Oda Y, Kikuchi H, Hatanaka M. Gene expression of fibroblast growth factors in human gliomas and meningiomas: demonstration of cellular source of basic fibroblast growth factor mRNA and peptide in tumor tissues. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5710–5714. [PMC free article] [PubMed]
  • Statuto M, Ennas MG, Zamboni G, Bonetti F, Pea M, Bernardello F, Pozzi A, Rusnati M, Gualandris A, Presta M. Basic fibroblast growth factor in human pheochromocytoma: a biochemical and immunohistochemical study. Int J Cancer. 1993 Jan 2;53(1):5–10. [PubMed]
  • Wang Y, Becker D. Antisense targeting of basic fibroblast growth factor and fibroblast growth factor receptor-1 in human melanomas blocks intratumoral angiogenesis and tumor growth. Nat Med. 1997 Aug;3(8):887–893. [PubMed]
  • Yamanaka Y, Friess H, Buchler M, Beger HG, Uchida E, Onda M, Kobrin MS, Korc M. Overexpression of acidic and basic fibroblast growth factors in human pancreatic cancer correlates with advanced tumor stage. Cancer Res. 1993 Nov 1;53(21):5289–5296. [PubMed]
  • Hanahan D. Signaling vascular morphogenesis and maintenance. Science. 1997 Jul 4;277(5322):48–50. [PubMed]
  • Martiny-Baron G, Marmé D. VEGF-mediated tumour angiogenesis: a new target for cancer therapy. Curr Opin Biotechnol. 1995 Dec;6(6):675–680. [PubMed]
  • Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993 Apr 29;362(6423):841–844. [PubMed]
  • Saleh M, Stacker SA, Wilks AF. Inhibition of growth of C6 glioma cells in vivo by expression of antisense vascular endothelial growth factor sequence. Cancer Res. 1996 Jan 15;56(2):393–401. [PubMed]
  • Millauer B, Shawver LK, Plate KH, Risau W, Ullrich A. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature. 1994 Feb 10;367(6463):576–579. [PubMed]
  • Samoto K, Ikezaki K, Ono M, Shono T, Kohno K, Kuwano M, Fukui M. Expression of vascular endothelial growth factor and its possible relation with neovascularization in human brain tumors. Cancer Res. 1995 Mar 1;55(5):1189–1193. [PubMed]
  • Takahashi Y, Cleary KR, Mai M, Kitadai Y, Bucana CD, Ellis LM. Significance of vessel count and vascular endothelial growth factor and its receptor (KDR) in intestinal-type gastric cancer. Clin Cancer Res. 1996 Oct;2(10):1679–1684. [PubMed]
  • Mignatti P, Morimoto T, Rifkin DB. Basic fibroblast growth factor released by single, isolated cells stimulates their migration in an autocrine manner. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11007–11011. [PMC free article] [PubMed]
  • Mignatti P, Morimoto T, Rifkin DB. Basic fibroblast growth factor, a protein devoid of secretory signal sequence, is released by cells via a pathway independent of the endoplasmic reticulum-Golgi complex. J Cell Physiol. 1992 Apr;151(1):81–93. [PubMed]
  • Yeoman LC. An autocrine model for cell- and matrix-associated fibroblast growth factor. Oncol Res. 1993;5(12):489–499. [PubMed]
  • Chodak GW, Hospelhorn V, Judge SM, Mayforth R, Koeppen H, Sasse J. Increased levels of fibroblast growth factor-like activity in urine from patients with bladder or kidney cancer. Cancer Res. 1988 Apr 15;48(8):2083–2088. [PubMed]
  • Nguyen M, Watanabe H, Budson AE, Richie JP, Hayes DF, Folkman J. Elevated levels of an angiogenic peptide, basic fibroblast growth factor, in the urine of patients with a wide spectrum of cancers. J Natl Cancer Inst. 1994 Mar 2;86(5):356–361. [PubMed]
  • Li VW, Folkerth RD, Watanabe H, Yu C, Rupnick M, Barnes P, Scott RM, Black PM, Sallan SE, Folkman J. Microvessel count and cerebrospinal fluid basic fibroblast growth factor in children with brain tumours. Lancet. 1994 Jul 9;344(8915):82–86. [PubMed]
  • Kandel J, Bossy-Wetzel E, Radvanyi F, Klagsbrun M, Folkman J, Hanahan D. Neovascularization is associated with a switch to the export of bFGF in the multistep development of fibrosarcoma. Cell. 1991 Sep 20;66(6):1095–1104. [PubMed]
  • Baird A, Mormède P, Böhlen P. Immunoreactive fibroblast growth factor (FGF) in a transplantable chondrosarcoma: inhibition of tumor growth by antibodies to FGF. J Cell Biochem. 1986;30(1):79–85. [PubMed]
  • Gross JL, Herblin WF, Dusak BA, Czerniak P, Diamond MD, Sun T, Eidsvoog K, Dexter DL, Yayon A. Effects of modulation of basic fibroblast growth factor on tumor growth in vivo. J Natl Cancer Inst. 1993 Jan 20;85(2):121–131. [PubMed]
  • Hori A, Sasada R, Matsutani E, Naito K, Sakura Y, Fujita T, Kozai Y. Suppression of solid tumor growth by immunoneutralizing monoclonal antibody against human basic fibroblast growth factor. Cancer Res. 1991 Nov 15;51(22):6180–6184. [PubMed]
  • Czubayko F, Liaudet-Coopman ED, Aigner A, Tuveson AT, Berchem GJ, Wellstein A. A secreted FGF-binding protein can serve as the angiogenic switch in human cancer. Nat Med. 1997 Oct;3(10):1137–1140. [PubMed]
  • Rak J, Kerbel RS. bFGF and tumor angiogenesis--back in the limelight? Nat Med. 1997 Oct;3(10):1083–1084. [PubMed]
  • Goto F, Goto K, Weindel K, Folkman J. Synergistic effects of vascular endothelial growth factor and basic fibroblast growth factor on the proliferation and cord formation of bovine capillary endothelial cells within collagen gels. Lab Invest. 1993 Nov;69(5):508–517. [PubMed]
  • Coltrini D, Gualandris A, Nelli EE, Parolini S, Molinari-Tosatti MP, Quarto N, Ziche M, Giavazzi R, Presta M. Growth advantage and vascularization induced by basic fibroblast growth factor overexpression in endometrial HEC-1-B cells: an export-dependent mechanism of action. Cancer Res. 1995 Oct 15;55(20):4729–4738. [PubMed]
  • Malkusch W, Konerding MA, Klapthor B, Bruch J. A simple and accurate method for 3-D measurements in microcorrosion casts illustrated with tumour vascularization. Anal Cell Pathol. 1995 Jul;9(1):69–81. [PubMed]
  • Lametschwandtner A, Lametschwandtner U, Weiger T. Scanning electron microscopy of vascular corrosion casts--technique and applications: updated review. Scanning Microsc. 1990 Dec;4(4):889–941. [PubMed]
  • Gualandris A, Rusnati M, Belleri M, Nelli EE, Bastaki M, Molinari-Tosatti MP, Bonardi F, Parolini S, Albini A, Morbidelli L, et al. Basic fibroblast growth factor overexpression in endothelial cells: an autocrine mechanism for angiogenesis and angioproliferative diseases. Cell Growth Differ. 1996 Feb;7(2):147–160. [PubMed]
  • Sola Francesco, Gualandris Anna, Belleri Mirella, Giuliani Roberta, Coltrini Daniela, Bastaki Maria, Tosatti Maria Pia Molinari, Bonardi Fabrizio, Vecchi Annunciata, Fioretti Francesca, et al. Endothelial cells overexpressing basic fibroblast growth factor (FGF-2) induce vascular tumors in immunodeficient mice. Angiogenesis. 1997;1(1):102–116. [PubMed]
  • Zhang HT, Craft P, Scott PA, Ziche M, Weich HA, Harris AL, Bicknell R. Enhancement of tumor growth and vascular density by transfection of vascular endothelial cell growth factor into MCF-7 human breast carcinoma cells. J Natl Cancer Inst. 1995 Feb 1;87(3):213–219. [PubMed]
  • Yuan F, Chen Y, Dellian M, Safabakhsh N, Ferrara N, Jain RK. Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14765–14770. [PMC free article] [PubMed]
  • Vaupel P, Gabbert H. Evidence for and against a tumor type-specific vascularity. Strahlenther Onkol. 1986 Oct;162(10):633–638. [PubMed]
  • Gazit Y, Berk DA, Leunig M, Baxter LT, Jain RK. Scale-invariant behavior and vascular network formation in normal and tumor tissue. Phys Rev Lett. 1995 Sep 18;75(12):2428–2431. [PubMed]
  • Ingber DE, Folkman J. How does extracellular matrix control capillary morphogenesis? Cell. 1989 Sep 8;58(5):803–805. [PubMed]
  • Ingber DE, Folkman J. Mechanochemical switching between growth and differentiation during fibroblast growth factor-stimulated angiogenesis in vitro: role of extracellular matrix. J Cell Biol. 1989 Jul;109(1):317–330. [PMC free article] [PubMed]
  • Davis CM, Danehower SC, Laurenza A, Molony JL. Identification of a role of the vitronectin receptor and protein kinase C in the induction of endothelial cell vascular formation. J Cell Biochem. 1993 Feb;51(2):206–218. [PubMed]
  • Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science. 1994 Apr 22;264(5158):569–571. [PubMed]
  • Plopper GE, McNamee HP, Dike LE, Bojanowski K, Ingber DE. Convergence of integrin and growth factor receptor signaling pathways within the focal adhesion complex. Mol Biol Cell. 1995 Oct;6(10):1349–1365. [PMC free article] [PubMed]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...