Jul 13, 2011 - Oncology Updates (DeVita VT Jr. Hellman S, Rosenberg SA, eds), vol 7. Philadelphia: Lippincott, 1993, pp 1-14. Note. Received January 25 ...
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cycle regulation by a temperature-sensitive p53 protein. Genes Dev 5:151-159. 1991 Lane DP, Benchimol S: p53: oncogene or anti-oncogene? Genes Dev 4:1-8, 1990 Finlay CA, Hinds PW, Levine AJ: The p53 proto-oncogene can act as a suppressor of transformation. Cell 57:1083-1093, 1989 Nigro JM, Baker SJ, Preisinger AC, et al: Mutations in the p53 gene occur in diverse human tumour types. Nature 342:705-708, 1989 Caron de Fromentel C, Soussi T: TP53 tumor suppressor gene: a mode] for investigating human mutagenesis. Genes Chromosom Cancer 4:1-15, 1992 Harris CC: p53: at the crossroads of molecular carcinogenesis and risk assessment. Science 262:1980-1981, 1993 The Best Science of 1992. Time 4 January:62, 1992 Molecule of the Year—p53 sweeps through cancer research. Science 262:1958-1959, 1993 Kastan MB, Onyekwere O, Sidransky D, ct al: Participation of p53 protein in the cellular response to DNA damage. Cancer Res 51:63046311, 1991 Kastan MB, Zhan Q, el-Deiry WS, et al: A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxiatelangiectasia. Cell 71:587-597, 1992 Lane DP: Cancer. p53, guardian of the genome. Nature 358:15-16,
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Note Received January 25, 1994; accepted January 25. 1994.
Which Angiogenesis Factor Is Important?
Anton Wellstein* Polypeptide growth factors serve as signals in the modeling of tissues during embryonic development as well as in the maintenance of tissue homeostasis in the mature organism. During the growth and metastasis of solid tumors, these growth factors function as autocrine stimulators of the tumor cells and/or play a role in recruiting stromal tissue and blood supply to the expanding tumor mass [reviewed in (7-5)]. With this in mind, Nguyen et al. (4) report in this issue of the Journal that one of the strongest angiogenic factors, basic fibroblast growth factor (bFGF), can be detected at elevated levels in urine samples from cancer patients. Forty-four percent of patients with active tumors from a wide variety of origins (e.g., breast, prostate, brain, lung, and lymphoma) showed an increase in urinary bFGF levels and this increase was the most pronounced in patients with active metastatic disease. In a subset of patients, this elevation was quenched on successful treatment of the patients' tumors. This report is the most recent one originating from the laboratory of Dr. J. Folkman, who has been a pioneer in angiogenesis research and who has demonstrated the significance of blood supply for tumor growth and metastasis (5). Clinical studies from his laboratory and from others (6-/5) have provided impressive evidence that the number of blood vessels detected in a primary tumor is an independent prognostic indicator of the outcome of the disease and is related to the rate of metastasis of tumors of different origin.
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Unfortunately, the answer to this question will remain very complex. Tissue-specific regulation of vasculogenesis and angiogenesis during embryonic and postnatal development as well as maintenance of blood vessels in the adult requires the biological activities of different growth factors {2,5). In principle, tumor cells can resort to any of these angiogenesis factors and can upregulate the respective genes during their transformation (5). A conservative estimate indicates that more than a dozen distinct protein products are currently known to induce proliferation of endothelial cells in vitro and/or angiogenesis in vivo. The most prominent and best studied angiogenesis factors are members of the fibroblast growth factor (FGF) family {14,15), but transforming growth factor-a (TGF-a), epidermal growth factor (EGF) {16), hepatocyte growth factor (77), vascular endothelial growth factor (VEGF) (75), pleiotrophin (79), and interleukin 4 (20) also qualify as potential tumor angiogenesis factors. Any combination of these proteins may be found expressed in tumor tissues or in tumor cell lines (5). Thus, it is difficult to decipher which ones are only innocent bystanders and which ones actively drive the rate-limiting tumor angiogenesis and are therefore not only diagnostic markers but also potential therapeutic targets (27). It can be expected that in the next few years the tools will be available to specifically target individual angiogenesis factors in vivo and thus demonstrate their relative contribution to angiogenesis in a given set of tumors. This approach is exemplified by recent experiments that used specific antibodies against VEGF and demonstrated that this factor was rate limiting for the growth of selected model tumors {18).
* Correspondence to: Anton Wellstein, M.D.. Ph.D., Vincent T. Lombardi Cancer Center. Department of Pharmacology, Georgetown University, 3800 Reservoir Rd.. N.W., Washington. DC 20007. See "Note" section following "References."
Journal of the National Cancer Institute, Vol. 86, No. 5, March 2, 1994
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Why Monitor Angiogenic Factors in Patients' Urine?
Urinary bFGF and TGF-ct-EGF in Cancer Patients
Conclusion Based on the current study with bFGF and other studies with TGF-a-EGF, the monitoring of angiogenesis factors in the urine of cancer patients is a very promising surrogate marker of therapeutic efficacy and could support the assessment of a patient's prognosis.
(/) Sporn MB. Roberts AB: Peptide growth factors are multifunctional. Nature 332:217-219. 1988 (2) Folkman J. Klagsbrun M: Angiogenic factors. Science 235:442-447. 1987 (J) Cross M, Dexter TM: Growth factors in development, transformation. and tumorigenesis. Cell 64:271-280. 1991 (4) Nguyen M, Watanabe H, Budson AE. et al: 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 86:356361. 1994 (5) Folkman J, Shing Y: Angiogenesis. J Biol Chem 267:10931-10934, 1992 (6) Weidner N. Semple JP, Welch WR, et al: Tumor angiogenesis and metastasis—correlation in invasive breast carcinoma. N Engl J Med 324:1-8. 1991 (7) Horak ER. Leek R, Klenk N, et al: Angiogenesis, assessed by platelet/ endothelial cell adhesion molecule antibodies, as indicator of node metastases and survival in breast cancer. Lancet 340:1120-1124, 1992 (8) Bosari S, Lee AK, DeLellis RA, et al: Microvessel quantitation and prognosis in invasive breast carcinoma. Hum Pathol 23:755-761, 1992 (9) Weidner N, Folkman J, Pozza F, et al: Tumor angiogenesis a new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst 84:1875-1887, 1992 (10) Toi M, Kashitani J. Tominaga T: Tumor angiogenesis is an independent prognostic indicator in primary breast carcinoma. Int J Cancer 55:371-374, 1993 (//) Macchiarini P, Fontanini G, Hardin MI, et al: Relation of neovascularisation to metastasis of non—small-cell lung cancer. Lancet 340:145-146, 1992 (12) Weidner N, Carroll PR, Flax J, et al: Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 143:401409, 1993 (13) Gasparini G, Weidner N, Maluta S, et al: Intratumoral microvessel density and p53 protein: correlation with metastasis in head-and-neck squamous-cell carcinoma. Int J Cancer 55 739-744, 1993 (14) Burgess WH, Maciag T: The heparin-binding (fibroblast) growth factor family of proteins. Annu Rev Biochem 58:575-606, 1989 (15) Baird A, Klagsbrun M: The fibroblast growth factor family. Cancer Cells 3:239-243, 1991 (IS) Schreiber AB, Winkler ME, Derynck R: Transforming growth factoralpha: a more potent angiogenic mediator than epidermal growth factor. Science 232:1250-1253, 1986 (17) Weidner KM. Hartmann G, Sachs M, et al: Properties and functions of scatter factor/hepatocyte growth factor and its receptor c-Met. Am J Respir Cell Mol Biol 8:229-237, 1993 (18) Kim KJ, Li B, Winer J, et al: Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362:841-844, 1993 (19) Fang W, Hartmann N, Chow DT, et al: Pleiotrophin stimulates fibroblasls and endolhelial and epithelial cells and is expressed in human cancer. J Biol Chem 267:25889-25897, 1992 (20) Toi M, Harris AL, Bicknell R: Interleukin-4 is a potent mitogen for capillary endothelium. Biochem Biophys Res Commun 174:12871293, 1991 (21) Denekamp J: Review article: angiogenesis, neovascular proliferation and vascular pathophysiology as targets for cancer therapy. Br J Radiol 66:181-196, 1993 (22) Vlodavsky I. Bashkin P, Ishai-Michaeli R, et al: Sequestration and release of basic fibroblast growth factor. Ann N Y Acad Sci 638:207220, 1991 (23) Kiefer MC. Stephans JC. Crawford K, et al: Ligand-affinity cloning and structure of a cell surface heparan sulfate proteoglycan that binds basic fibroblast growth factor. Proc Natl Acad Sci U S A 87:69856989. 1990 (24) Stromberg K, Duffy M. Fritsch C, et al: Comparison of urinary transforming growth factor-alpha in women with disseminated breast cancer and healthy control women. Cancer Detect Prcv 15:277-283, 1991 (25) Kanno H, Chiba Y, Kyuma Y. et al: Urinary epidermal growth factor in patients with gliomas: significance of the factor as a glial tumor marker. J Neurosurg 79:408-413. 1993
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Short of being able to demonstrate the relative contribution of a given factor to the growth of a particular tumor, Nguyen et al. (4) focused on one of the most active angiogenesis factors, bFGF (5,14,15). The bFGF is the best studied molecule of the expanding FGF family of related molecules [FGF-1 = acidic FGF = aFGF; FGF-3 = int-2; FGF-4 = K-FGF/hst-1; and FGF-5 and FGF-6 = hst-2 (74,75)]. The aFGF and bFGF are unique in the family because they do not contain secretory signal sequences and are either stored inside producing cells or deposited in the basement membrane or extracellular matrix (22). High concentrations of biologically active bFGF are found in extracts of normal embryonic and adult tissues as well as in tumor tissues of different origin (14). The biological activities of bFGF are quenched by tight binding to heparan sulfate proteoglycans present in the extracellular matrix (22,23), resulting, for example, in a lack of angiogenic activity in normal adult tissues. It is only partly understood how bFGF becomes activated in embryonic or in tumor tissues that require angiogenesis for their growth. One established mechanism that can release bFGF from its storage site is the digestion of the glycosaminoglycan portion of the cell attachment molecule by heparinases or by proteases (22). Alternatively, bFGF can be released by carrier molecules such as heparin. Finally, bFGF is released from mechanically wounded or radiation-damaged endothelial cells (22). It is conceivable that the elevated levels of bFGF described for cancer patients with active disease (4) are indicators of tissue remodeling due to tumor expansion and invasion. Active tumors would thus induce the release of significant amounts of locally present bFGF that can then spill over into the circulation and appear in the urine of patients. Successful treatment of the tumors would quench this process. As Nguyen et al. (4) point out, therapeutic monitoring and use for prognosis appear to be some of the best applications of their current assay for urinary bFGF. Parallel detection of other candidate angiogenesis factors in urinary samples to generate an "angiogenic profile" (4) for patients appears to be a worthwhile goal. For example, in studies from other laboratories (24), TGF-a-EGF showed a significant increase in urine samples from patients with disseminated breast cancer relative to normal controls. In patients with glioma, urinary EGF levels were increased in parallel with disease progression and were reduced to normal after successful therapeutic intervention (25), which was very similar to the current findings of Nguyen et al. (4).
References
Note Manuscript received January 28, 1994; accepted January 28, 1994.
Journal of the National Cancer Institute, Vol. 86, No. 5, March 2, 1994
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