Chapter 6 Conclusion and implications
6.3 C ONCLUSION
6.3 Conclusion
After the clinical observation that TSP-1 plays an important role in the regulation of angiogenic switch during cervical carcinogenesis (Wu MP et al. 2004), we further elucidate the cause-effect relationship between TSP-1 and tumor-stroma
interaction (Wu MP et al. 2008). The in vivo xenotransplant animal model elucidates the anti-angiogenic effect of TSP-1 and the ability to modulate tumor-stroma interaction morphologically and functionally. Furthermore, TSP-1 reduces the stroma reaction by changing the behaviors of stromal cells, i.e.
myofibroblasts in multicellular Matrigel co-culture model. Much work on the biologic mechanisms of fibroblast recruitment is needed, but the present study may offer the evidence that TSP-1 can change the tumor-stroma reaction during tumor progression by acting on the activity of myofibroblasts (Wu MP et al. 2008).
It suggests that fibroblasts could be used as a biologic tracer of cancer cells and could act as an efficient drug delivery system to prevent or slow the local growth of cancer cells. Elucidation of the mechanism by which fibroblasts are recruited into cancer stroma could lead to new insights into not only the mechanisms of cancer progression but also strategies for cancer treatment. A better understanding of stromal contributions to cancer progression will likely increase our awareness of the importance of the combinatorial signals that support and promote growth, dedifferentiation, invasion, and ectopic survival and eventually result in the identification of new therapeutics targeting the stroma (De Wever O and Mareel M 2003).
References
1. Abulafia O, Triest WE, Sherer DM. Angiogenesis in squamous cell carcinoma in situ and microinvasive carcinoma of the uterine cervix. Obstet Gynecol 88(6):927-932;1996.
2. Abulafia O, Triest WE, Sherer DM. Angiogenesis in malignancies of the female genital tract. Gynecol Oncol 72(2):220-231;1999.
3. Achilles EG, Fernandez A, Allred EN, Kisker O, Udagawa T, Beecken WD, et al. Heterogeneity of angiogenic activity in a human liposarcoma: a proposed mechanism for "no take" of human tumors in mice. J Natl Cancer Inst
93(14):1075-1081;2001.
4. Albini A, Iwamoto Y, Kleinman HK, Martin GR, Aaronson SA, Kozlowski JM, et al. A rapid in vitro assay for quantitating the invasive potential of tumor cells.
Cancer Res 47(12):3239-3245;1987.
5. Albo D, Shinohara T, Tuszynski GP. Up-regulation of matrix metalloproteinase 9 by thrombospondin 1 in gastric cancer. J Surg Res 108(1):51-60;2002.
6. Alves F, Borchers U, Padge B, Augustin H, Nebendahl K, Kloppel G, et al.
Inhibitory effect of a matrix metalloproteinase inhibitor on growth and spread of human pancreatic ductal adenocarcinoma evaluated in an orthotopic severe combined immunodeficient (SCID) mouse model. Cancer Lett
165(2):161-170;2001.
7. Amatangelo MD, Bassi DE, Klein-Szanto AJ, Cukierman E. Stroma-derived three-dimensional matrices are necessary and sufficient to promote
desmoplastic differentiation of normal fibroblasts. Am J Pathol 167(2):475-488;2005.
8. Annes JP, Munger JS, Rifkin DB. Making sense of latent TGFbeta activation. J Cell Sci 116(Pt 2):217-224;2003.
9. Asch AS, Tepler J, Silbiger S, Nachman RL. Cellular attachment to
thrombospondin. Cooperative interactions between receptor systems. J Biol
Chem 266(3):1740-1745;1991.
10. Baenziger NL, Brodie GN, Majerus PW. A thrombin-sensitive protein of human platelet membranes. Proc Natl Acad Sci U S A 68(1):240-243;1971.
11. Barcellos-Hoff MH and Ravani SA. Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells. Cancer Res 60(5):1254-1260;2000.
12. Bein K and Simons M. Thrombospondin type 1 repeats interact with matrix metalloproteinase 2. Regulation of metalloproteinase activity. J Biol Chem 275(41):32167-32173;2000.
13. Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2(10):737-744;2000.
14. Bertin N, Clezardin P, Kubiak R, Frappart L. Thrombospondin-1 and -2 messenger RNA expression in normal, benign, and neoplastic human breast tissues: correlation with prognostic factors, tumor angiogenesis, and
fibroblastic desmoplasia. Cancer Res 57(3):396-399;1997.
15. Bertolini F, Paul S, Mancuso P, Monestiroli S, Gobbi A, Shaked Y, et al.
Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. Cancer Res 63(15):4342-4346;2003.
16. Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S, et al.
TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303(5659):848-851;2004.
17. Bierie B and Moses HL. TGF-beta and cancer. Cytokine Growth Factor Rev 17(1-2):29-40;2006.
18. Bisacchi D, Benelli R, Vanzetto C, Ferrari N, Tosetti F, Albini A.
Anti-angiogenesis and angioprevention: mechanisms, problems and perspectives. Cancer Detect Prev 27(3):229-238;2003.
19. Bissell MJ and Radisky D. Putting tumours in context. Nat Rev Cancer 1(1):46-54;2001.
20. Bocci G, Francia G, Man S, Lawler J, Kerbel RS. Thrombospondin 1, a
mediator of the antiangiogenic effects of low-dose metronomic chemotherapy.
Proc Natl Acad Sci U S A 100(22):12917-12922;2003.
21. Bocci G, Nicolaou KC, Kerbel RS. Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective
antiangiogenic window for various chemotherapeutic drugs. Cancer Res 62(23):6938-6943;2002.
22. Boehm T, Folkman J, Browder T, O'Reilly MS. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 390(6658):404-407;1997.
23. Bornstein P. Thrombospondins: structure and regulation of expression.
FASEB J 6(14):3290-3299;1992.
24. Bornstein P. Matricellular proteins: an overview. Matrix Biol 19(7):555-556;2000.
25. Bornstein P. Thrombospondins as matricellular modulators of cell function. J Clin Invest 107(8):929-934;2001.
26. Bornstein P, Armstrong LC, Hankenson KD, Kyriakides TR, Yang Z.
Thrombospondin 2, a matricellular protein with diverse functions. Matrix Biol 19(7):557-568;2000a.
27. Bornstein P, Kyriakides TR, Yang Z, Armstrong LC, Birk DE. Thrombospondin 2 modulates collagen fibrillogenesis and angiogenesis. J Investig Dermatol Symp Proc 5(1):61-66;2000b.
28. Bornstein P and Sage EH. Matricellular proteins: extracellular modulators of cell function. Curr Opin Cell Biol 14(5):608-616;2002.
29. Bouck N. Tumor angiogenesis: the role of oncogenes and tumor suppressor genes. Cancer Cells 2(6):179-185;1990.
30. Bremer GL, Tiebosch AT, van der Putten HW, Schouten HJ, de Haan J, Arends JW. Tumor angiogenesis: an independent prognostic parameter in cervical cancer. Am J Obstet Gynecol 174(1 Pt 1):126-131;1996.
31. Brooks PC, Stromblad S, Sanders LC, von Schalscha TL, Aimes RT,
Stetler-Stevenson WG, et al. Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3. Cell 85(5):683-693;1996.
32. Browder T, Butterfield CE, Kraling BM, Shi B, Marshall B, O'Reilly MS, et al.
Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60(7):1878-1886;2000.
33. Brown EJ and Frazier WA. Integrin-associated protein (CD47) and its ligands.
Trends Cell Biol 11(3):130-135;2001.
34. Bunone G, Vigneri P, Mariani L, Buto S, Collini P, Pilotti S, et al. Expression of angiogenesis stimulators and inhibitors in human thyroid tumors and
correlation with clinical pathological features. Am J Pathol 155(6):1967-1976;1999.
35. Bussolati B, Assenzio B, Deregibus MC, Camussi G. The proangiogenic phenotype of human tumor-derived endothelial cells depends on
thrombospondin-1 downregulation via phosphatidylinositol 3-kinase/Akt pathway. J Mol Med 84(10):852-863;2006.
36. Bussolino F, Mantovani A, Persico G. Molecular mechanisms of blood vessel formation. Trends Biochem Sci 22(7):251-256;1997.
37. Calzada MJ, Zhou L, Sipes JM, Zhang J, Krutzsch HC, Iruela-Arispe ML, et al.
Alpha4beta1 integrin mediates selective endothelial cell responses to thrombospondins 1 and 2 in vitro and modulates angiogenesis in vivo. Circ Res 94(4):462-470;2004.
38. Campbell SC, Volpert OV, Ivanovich M, Bouck NP. Molecular mediators of angiogenesis in bladder cancer. Cancer Res 58(6):1298-1304;1998.
39. Cantu De Leon D, Lopez-Graniel C, Frias Mendivil M, Chanona Vilchis G, Gomez C, De La Garza Salazar J. Significance of microvascular density (MVD) in cervical cancer recurrence. Int J Gynecol Cancer 13(6):856-862;2003.
40. Carmeliet P and Jain RK. Angiogenesis in cancer and other diseases. Nature 407(6801):249-257;2000.
41. Castle V, Varani J, Fligiel S, Prochownik EV, Dixit V. Antisense-mediated reduction in thrombospondin reverses the malignant phenotype of a human squamous carcinoma. J Clin Invest 87(6):1883-1888;1991.
42. Castle VP, Ou X, O'Rourke K, Dixit VM. High level thrombospondin 1 expression in two NIH 3T3 cloned lines confers serum- and
anchorage-independent growth. J Biol Chem 268(4):2899-2903;1993.
43. Chen H, Herndon ME, Lawler J. The cell biology of thrombospondin-1. Matrix Biol 19(7):597-614;2000.
44. Chen PS, Wang MY, Wu SN, Su JL, Hong CC, Chuang SE, et al. CTGF enhances the motility of breast cancer cells via an
integrin-alphavbeta3-ERK1/2-dependent S100A4-upregulated pathway. J Cell Sci 120(Pt 12):2053-2065;2007.
45. Chen S, Takanashi S, Zhang Q, Xiong W, Zhu S, Peters EC, et al. Reversine increases the plasticity of lineage-committed mammalian cells. Proc Natl Acad Sci U S A 104(25):10482-10487;2007.
46. Chen S, Zhang Q, Wu X, Schultz PG, Ding S. Dedifferentiation of lineage-committed cells by a small molecule. J Am Chem Soc 126(2):410-411;2004.
47. Cheng WF, Chen CA, Lee CN, Wei LH, Hsieh FJ, Hsieh CY. Vascular
endothelial growth factor and prognosis of cervical carcinoma. Obstet Gynecol 96(5 Pt 1):721-726;2000.
48. Cheng WF, Lee CN, Chu JS, Chen CA, Chen TM, Shau WY, et al. Vascularity index as a novel parameter for the in vivo assessment of angiogenesis in
patients with cervical carcinoma. Cancer 85(3):651-657;1999.
49. Chlenski A, Guerrero LJ, Yang Q, Tian Y, Peddinti R, Salwen HR, et al.
SPARC enhances tumor stroma formation and prevents fibroblast activation.
Oncogene;2007a.
50. Chlenski A, Guerrero LJ, Yang Q, Tian Y, Peddinti R, Salwen HR, et al.
SPARC enhances tumor stroma formation and prevents fibroblast activation.
Oncogene 26(31):4513-4522;2007b.
51. Chou CY, Shen MR, Wu SN. Volume-sensitive chloride channels associated with human cervical carcinogenesis. Cancer Res 55(24):6077-6083;1995.
52. Chou CY, Wang ST, Kuo HC, Tzeng CC, Yao BL. Serum level of squamous cell carcinoma antigen and tumor size are useful to identify preoperatively patients at high risk of cervical cancer. Cancer 74(9):2497-2501;1994.
53. Cintorino M, Bellizzi de Marco E, Leoncini P, Tripodi SA, Xu LJ, Sappino AP, et al. Expression of alpha-smooth-muscle actin in stromal cells of the uterine cervix during epithelial neoplastic changes. Int J Cancer 47(6):843-846;1991.
54. Clezardin P, Frappart L, Clerget M, Pechoux C, Delmas PD. Expression of thrombospondin (TSP1) and its receptors (CD36 and CD51) in normal, hyperplastic, and neoplastic human breast. Cancer Res
53(6):1421-1430;1993.
55. Colorado PC, Torre A, Kamphaus G, Maeshima Y, Hopfer H, Takahashi K, et al.
Anti-angiogenic cues from vascular basement membrane collagen. Cancer Res 60(9):2520-2526;2000.
56. Cooper RA, Carrington BM, Loncaster JA, Todd SM, Davidson SE, Logue JP, et al. Tumour oxygenation levels correlate with dynamic contrast-enhanced magnetic resonance imaging parameters in carcinoma of the cervix. Radiother Oncol 57(1):53-59;2000.
57. Coussens LM and Werb Z. Inflammation and cancer. Nature 420(6917):860-867;2002.
58. Crawford SE, Stellmach V, Murphy-Ullrich JE, Ribeiro SM, Lawler J, Hynes RO, et al. Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell 93(7):1159-1170;1998.
59. Dameron KM, Volpert OV, Tainsky MA, Bouck N. Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science
265(5178):1582-1584;1994.
60. Dawson DW, Pearce SF, Zhong R, Silverstein RL, Frazier WA, Bouck NP.
CD36 mediates the In vitro inhibitory effects of thrombospondin-1 on endothelial cells. J Cell Biol 138(3):707-717;1997.
61. de Fraipont F, El Atifi M, Gicquel C, Bertagna X, Chambaz EM, Feige JJ.
Expression of the angiogenesis markers vascular endothelial growth factor-A, thrombospondin-1, and platelet-derived endothelial cell growth factor in
human sporadic adrenocortical tumors: correlation with genotypic alterations.
J Clin Endocrinol Metab 85(12):4734-4741;2000.
62. de Fraipont F, Nicholson AC, Feige JJ, Van Meir EG. Thrombospondins and tumor angiogenesis. Trends Mol Med 7(9):401-407;2001.
63. De Wever O and Mareel M. Role of tissue stroma in cancer cell invasion. J Pathol 200(4):429-447;2003.
64. De Wever O, Nguyen QD, Van Hoorde L, Bracke M, Bruyneel E, Gespach C, et al. Tenascin-C and SF/HGF produced by myofibroblasts in vitro provide convergent pro-invasive signals to human colon cancer cells through RhoA and Rac. Faseb J 18(9):1016-1018;2004a.
65. De Wever O, Westbroek W, Verloes A, Bloemen N, Bracke M, Gespach C, et al. Critical role of N-cadherin in myofibroblast invasion and migration in vitro stimulated by colon-cancer-cell-derived TGF-beta or wounding. J Cell Sci 117(Pt 20):4691-4703;2004b.
66. Dellas A, Moch H, Schultheiss E, Feichter G, Almendral AC, Gudat F, et al.
Angiogenesis in cervical neoplasia: microvessel quantitation in precancerous
lesions and invasive carcinomas with clinicopathological correlations. Gynecol Oncol 67(1):27-33;1997.
67. Desmouliere A, Geinoz A, Gabbiani F, Gabbiani G. Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol 122(1):103-111;1993.
68. Desmouliere A, Guyot C, Gabbiani G. The stroma reaction myofibroblast: a key player in the control of tumor cell behavior. Int J Dev Biol
48(5-6):509-517;2004.
69. Di Leo S, Caschetto S, Garozzo G, Nuciforo G, Cassaro N, Meli MT, et al.
Angiogenesis as a prognostic factor in cervical carcinoma. Eur J Gynaecol Oncol 19(2):158-162;1998.
70. Dimanche-Boitrel MT, Vakaet L, Jr., Pujuguet P, Chauffert B, Martin MS, Hammann A, et al. In vivo and in vitro invasiveness of a rat colon-cancer cell line maintaining E-cadherin expression: an enhancing role of
tumor-associated myofibroblasts. Int J Cancer 56(4):512-521;1994.
71. Dixit VM, Hennessy SW, Grant GA, Rotwein P, Frazier WA. Characterization of a cDNA encoding the heparin and collagen binding domains of human thrombospondin. Proc Natl Acad Sci U S A 83(15):5449-5453;1986.
72. Dobbs SP, Hewett PW, Johnson IR, Carmichael J, Murray JC. Angiogenesis is associated with vascular endothelial growth factor expression in cervical intraepithelial neoplasia. Br J Cancer 76(11):1410-1415;1997.
73. Doyen V, Rubio M, Braun D, Nakajima T, Abe J, Saito H, et al.
Thrombospondin 1 is an autocrine negative regulator of human dendritic cell activation. J Exp Med 198(8):1277-1283;2003.
74. Eberhard A, Kahlert S, Goede V, Hemmerlein B, Plate KH, Augustin HG.
Heterogeneity of angiogenesis and blood vessel maturation in human tumors:
implications for antiangiogenic tumor therapies. Cancer Res
60(5):1388-1393;2000.
75. Ellenson LH and Wu TC. Focus on endometrial and cervical cancer. Cancer Cell 5(6):533-538;2004.
76. Ezzell C. Starving tumors of their lifeblood. Sci Am 279(4):33-34;1998.
77. Fang J, Shing Y, Wiederschain D, Yan L, Butterfield C, Jackson G, et al. Matrix metalloproteinase-2 is required for the switch to the angiogenic phenotype in a tumor model. Proc Natl Acad Sci U S A 97(8):3884-3889;2000.
78. Feldman AL, Alexander HR, Jr., Bartlett DL, Kranda KC, Miller MS, Costouros NG, et al. A prospective analysis of plasma endostatin levels in colorectal cancer patients with liver metastases. Ann Surg Oncol 8(9):741-745;2001a.
79. Feldman AL, Alexander HR, Jr., Yang JC, Linehan WM, Eyler RA, Miller MS, et al. Prospective analysis of circulating endostatin levels in patients with renal cell carcinoma. Cancer 95(8):1637-1643;2002.
80. Feldman AL, Pak H, Yang JC, Alexander HR, Jr., Libutti SK. Serum endostatin levels are elevated in patients with soft tissue sarcoma. Cancer
91(8):1525-1529;2001b.
81. Feldman AL, Tamarkin L, Paciotti GF, Simpson BW, Linehan WM, Yang JC, et al. Serum endostatin levels are elevated and correlate with serum vascular endothelial growth factor levels in patients with stage IV clear cell renal cancer.
Clin Cancer Res 6(12):4628-4634;2000.
82. Fidler IJ. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer 3(6):453-458;2003.
83. Fidler IJ and Ellis LM. Chemotherapeutic drugs--more really is not better. Nat Med 6(5):500-502;2000.
84. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21):1182-1186;1971.
85. Folkman J. The role of angiogenesis in tumor growth. Semin Cancer Biol 3(2):65-71;1992.
86. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease.
Nat Med 1(1):27-31;1995a.
87. Folkman J. Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. N Engl J Med
333(26):1757-1763;1995b.
88. Folkman J. Tumor angiogenesis and tissue factor. Nat Med 2(2):167-168;1996.
89. Folkman J. Is tissue mass regulated by vascular endothelial cells? Prostate as the first evidence. Endocrinology 139(2):441-442;1998.
90. Folkman J. Angiogenesis and apoptosis. Semin Cancer Biol 13(2):159-167;2003a.
91. Folkman J. Fundamental concepts of the angiogenic process. Curr Mol Med 3(7):643-651;2003b.
92. Folkman J, Hahnfeldt P, Hlatky L. Cancer: looking outside the genome. Nat Rev Mol Cell Biol 1(1):76-79;2000.
93. Fontana A, Filleur S, Guglielmi J, Frappart L, Bruno-Bossio G, Boissier S, et al.
Human breast tumors override the antiangiogenic effect of stromal thrombospondin-1 in vivo. Int J Cancer 116(5):686-691;2005.
94. Framson PE and Sage EH. SPARC and tumor growth: where the seed meets the soil? J Cell Biochem 92(4):679-690;2004.
95. Franck-Lissbrant I, Haggstrom S, Damber JE, Bergh A. Testosterone stimulates angiogenesis and vascular regrowth in the ventral prostate in castrated adult rats. Endocrinology 139(2):451-456;1998.
96. Frazier WA. Thrombospondins. Curr Opin Cell Biol 3(5):792-799;1991.
97. Fukumura D, Xavier R, Sugiura T, Chen Y, Park EC, Lu N, et al. Tumor
induction of VEGF promoter activity in stromal cells. Cell 94(6):715-725;1998.
98. Gasparini G. Metronomic scheduling: the future of chemotherapy? Lancet Oncol 2(12):733-740;2001.
99. Gasparini G and Harris AL. Does improved control of tumour growth require an anti-cancer therapy targeting both neoplastic and intratumoral endothelial cells? Eur J Cancer 30A(2):201-206;1994.
100. Graflund M, Sorbe B, Hussein A, Bryne M, Karlsson M. The prognostic value of histopathologic grading parameters and microvessel density in patients with early squamous cell carcinoma of the uterine cervix. Int J Gynecol Cancer 12(1):32-41;2002.
101. Grossfeld GD, Ginsberg DA, Stein JP, Bochner BH, Esrig D, Groshen S, et al.
Thrombospondin-1 expression in bladder cancer: association with p53 alterations, tumor angiogenesis, and tumor progression. J Natl Cancer Inst 89(3):219-227;1997.
102. Guedez L, Rivera AM, Salloum R, Miller ML, Diegmueller JJ, Bungay PM, et al.
Quantitative assessment of angiogenic responses by the directed in vivo angiogenesis assay. Am J Pathol 162(5):1431-1439;2003.
103. Guidi AJ, Abu-Jawdeh G, Berse B, Jackman RW, Tognazzi K, Dvorak HF, et al.
Vascular permeability factor (vascular endothelial growth factor) expression and angiogenesis in cervical neoplasia. J Natl Cancer Inst
87(16):1237-1245;1995.
104. Guidolin D, Vacca A, Nussdorfer GG, Ribatti D. A new image analysis method based on topological and fractal parameters to evaluate the angiostatic activity of docetaxel by using the Matrigel assay in vitro. Microvasc Res
67(2):117-124;2004.
105. Guo N, Krutzsch HC, Inman JK, Roberts DD. Thrombospondin 1 and type I repeat peptides of thrombospondin 1 specifically induce apoptosis of
endothelial cells. Cancer Res 57(9):1735-1742;1997.
106. Hahnfeldt P, Panigrahy D, Folkman J, Hlatky L. Tumor development under angiogenic signaling: a dynamical theory of tumor growth, treatment response, and postvascular dormancy. Cancer Res 59(19):4770-4775;1999.
107. Hanahan D, Bergers G, Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 105(8):1045-1047;2000.
108. Hanahan D and Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86(3):353-364;1996.
109. Hanahan D and Weinberg RA. The hallmarks of cancer. Cell 100(1):57-70;2000.
110. Hasebe T, Sasaki S, Imoto S, Ochiai A. Proliferative activity of intratumoral fibroblasts is closely correlated with lymph node and distant organ metastases of invasive ductal carcinoma of the breast. Am J Pathol
156(5):1701-1710;2000.
111. Hawighorst H. Dynamic MR imaging in cervical carcinoma. Radiology 213(2):617-618;1999.
112. Hawighorst T, Oura H, Streit M, Janes L, Nguyen L, Brown LF, et al.
Thrombospondin-1 selectively inhibits early-stage carcinogenesis and angiogenesis but not tumor lymphangiogenesis and lymphatic metastasis in transgenic mice. Oncogene 21(52):7945-7956;2002.
113. Hawighorst T, Velasco P, Streit M, Hong YK, Kyriakides TR, Brown LF, et al.
Thrombospondin-2 plays a protective role in multistep carcinogenesis: a novel host anti-tumor defense mechanism. EMBO J 20(11):2631-2640;2001.
114. Hayashido Y, Nakashima M, Urabe K, Yoshioka H, Yoshioka Y, Hamana T, et al. Role of stromal thrombospondin-1 in motility and proteolytic activity of oral squamous cell carcinoma cells. Int J Mol Med 12(4):447-452;2003.
115. Hlatky L, Hahnfeldt P, Folkman J. Clinical application of antiangiogenic therapy: microvessel density, what it does and doesn't tell us. J Natl Cancer Inst 94(12):883-893;2002.
116. Hlatky L, Tsionou C, Hahnfeldt P, Coleman CN. Mammary fibroblasts may influence breast tumor angiogenesis via hypoxia-induced vascular endothelial
growth factor up-regulation and protein expression. Cancer Res 54(23):6083-6086;1994.
117. Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U, Vaupel P. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 56(19):4509-4515;1996.
118. Hsu KF, Su JM, Huang SC, Cheng YM, Kang CY, Shen MR, et al.
Three-dimensional power Doppler imaging of early-stage cervical cancer.
Ultrasound Obstet Gynecol 24(6):664-671;2004.
119. Hsu SC, Volpert OV, Steck PA, Mikkelsen T, Polverini PJ, Rao S, et al.
Inhibition of angiogenesis in human glioblastomas by chromosome 10 induction of thrombospondin-1. Cancer Res 56(24):5684-5691;1996.
120. Hugo C. The thrombospondin 1-TGF-beta axis in fibrotic renal disease.
Nephrol Dial Transplant 18(7):1241-1245;2003.
121. Isenberg JS, Calzada MJ, Zhou L, Guo N, Lawler J, Wang XQ, et al.
Endogenous thrombospondin-1 is not necessary for proliferation but is permissive for vascular smooth muscle cell responses to platelet-derived growth factor. Matrix Biol 24(2):110-123;2005a.
122. Isenberg JS, Ridnour LA, Perruccio EM, Espey MG, Wink DA, Roberts DD.
Thrombospondin-1 inhibits endothelial cell responses to nitric oxide in a cGMP-dependent manner. Proc Natl Acad Sci U S A
102(37):13141-13146;2005b.
123. Ishii G, Sangai T, Ito T, Hasebe T, Endoh Y, Sasaki H, et al. In vivo and in vitro characterization of human fibroblasts recruited selectively into human cancer stroma. Int J Cancer 117(2):212-220;2005.
124. Jendraschak E and Sage EH. Regulation of angiogenesis by SPARC and angiostatin: implications for tumor cell biology. Semin Cancer Biol
7(3):139-146;1996.
125. Jimenez B, Volpert OV, Crawford SE, Febbraio M, Silverstein RL, Bouck N.
Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nat Med 6(1):41-48;2000.
126. Jin RJ, Kwak C, Lee SG, Lee CH, Soo CG, Park MS, et al. The application of an anti-angiogenic gene (thrombospondin-1) in the treatment of human prostate cancer xenografts. Cancer Gene Ther 7(12):1537-1542;2000.
127. Kakeji Y and Teicher BA. Preclinical studies of the combination of angiogenic inhibitors with cytotoxic agents. Invest New Drugs 15(1):39-48;1997.
128. Kalas W, Yu JL, Milsom C, Rosenfeld J, Benezra R, Bornstein P, et al.
Oncogenes and Angiogenesis: down-regulation of thrombospondin-1 in normal fibroblasts exposed to factors from cancer cells harboring mutant ras.
Cancer Res 65(19):8878-8886;2005.
129. Kalluri R. Basement membranes: structure, assembly and role in tumour angiogenesis. Nat Rev Cancer 3(6):422-433;2003.
130. Kamen BA, Rubin E, Aisner J, Glatstein E. High-time chemotherapy or high time for low dose. J Clin Oncol 18(16):2935-2937;2000.
131. Kawahara N, Ono M, Taguchi K, Okamoto M, Shimada M, Takenaka K, et al.
Enhanced expression of thrombospondin-1 and hypovascularity in human cholangiocarcinoma. Hepatology 28(6):1512-1517;1998.
132. Kawataki T, Naganuma H, Sasaki A, Yoshikawa H, Tasaka K, Nukui H.
Correlation of thrombospondin-1 and transforming growth factor-beta
expression with malignancy of glioma. Neuropathology 20(3):161-169;2000.
133. Kazuno M, Tokunaga T, Oshika Y, Tanaka Y, Tsugane R, Kijima H, et al.
Thrombospondin-2 (TSP2) expression is inversely correlated with vascularity
Thrombospondin-2 (TSP2) expression is inversely correlated with vascularity