Angiogenese, Lymphangiogenese und Tumorprogression

Zusammenfassung

Angiogenese, die Entwicklung neuer Blutgefäße, spielt beim Wachstum und der Metastasierung von malignen Tumoren eine essenzielle Rolle. Der Übergang von der prävaskulären Phase, in der Tumorzellen ohne die Bildung neuer Blutgefäße proliferieren, auf die vaskuläre Phase, in der ab einer Tumorgröße von 2-3 Millimetern Angiogenese induziert wird („angiogenic switch”), kann invasivem Wachstum und Metastasierung sogar vorausgehen. Es wird angenommen, dass die Entwicklung neuer Blutgefäße durch eine Veränderung des Gleichgewichts zwischen pro- und antiangiogenen Faktoren induziert wird. Ein Schwerpunkt dieser Übersicht ist die Rolle zweier potenter, endogener Angiogeneseinhibitoren, Thrombospondin-(TSP-)1 und TSP-2, für die Entwicklung und Progression von Tumoren zu charakterisieren.

Durch die Identifizierung lymphatischer Wachstumsfaktoren sowie neuer spezifischer Marker für Lymphgefäße wurde es möglich die aktive Beteiligung des lymphatischen Gefäßsystems bei der Metastasierung maligner Tumoren nachzuweisen. Endogene Lymphangiogenesehemmer sind bisher noch nicht beschrieben worden. Welche Funktion bekannte endogene Angiogeneseinhibitoren für die Regulation der Lymphangiogenese haben ist bislang unklar.

Die bisherigen Erkenntnisse zeigen, dass Angiogeneseinhibitoren spezifisch die Tumorprogression, nicht aber die Umwandlung prämaligner Vorstufen in maligne Tumoren blockieren. Angiogeneseinhibitoren können dabei elektive Effekte auf die Neubildung von Blut- nicht aber Lymphgefäßen haben. Diese experimentellen Ergebnisse sind für die strategische Entwicklung und den klinischen Einsatz von Angiogeneseinhibitoren von Bedeutung, denn sie belegen, dass ein früher Einsatz von Inhibitoren während der Tumorprogression sowie eine Kombination mit spezifischen Inhibitoren der Lymphangiogenese effektiv sein könnte.

Abstract

Angiogenesis plays an important role for the growth and metastasis of malignant tumors. The “angiogenic switch” may even precede the development of other traits that contribute to the malignant phenotype. The switch to the angiogenic phenotype is thought to be induced by a change in the balance of positive and negative regulators of angiogenesis. The main emphasis of this review is to discuss the role of two potent endogenous inhibitors, thrombospondin-(TSP-)1 and TSP-2, for the development and progression of tumors.

The recent identification of specific growth factors for lymphatic vessels and of new lymphatic-specific markers provided evidence for an active role of the lymphatic system during the metastasis process. Endogenous inhibitors of lymphangiogenesis have not yet been detected and until recently it was unclear whether or not the known endogenous angiogenesis inhibitors may also have some additional effects on lymphangiogenesis.

The data provided indicate that angiogenesis inhibitors specifically inhibit tumor progression but fail to block the conversion of premalignant to malignant tumors. Moreover, angiogenesis inhibitors may have some elective effects on the formation of blood vessels but not on lymphatic vessels. These results will have implications for the further development and clinical use of angiogenesis inhibitors since they indicate that inhibitors might most efficiently be used to target early stages of tumor progression and in combination with specific inhibitors of lymphangiogenesis.

Schlüsselwörter

TSP-1 - TSP-2 - LYVE-1 - Prox1 - Karzinogenese - Metastasierung

Key words

TSP-1 - TSP-2 - LYVE-1 - Prox1 - carcinogenesis - metastasis

Literatur

• 1 Ahmad S A, Liu W, Jung Y D, Fan F, Wilson M, Reinmuth N, Shaheen R M, Bucana C D, Ellis L M. The effects of angiopoietin-1 and -2 on tumor growth and angiogenesis in human colon cancer.  Cancer Res. 2001;  61 1255-1259
• 2 Balmain A, Harris C C. Carcinogenesis in mouse and human cells: parallels and paradoxes.  Carcinogenesis. 2000;  21 371-377
• 3 Banerji S, Ni J, Wang S X, Clasper S, Su J, Tammi R, Jones M, Jackson D G. LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan.  J Cell Biol. 1999;  144 789-801
• 4 Bleuel K, Popp S, Fusenig N E, Stanbridge E J, Boukamp P. Tumor suppression in human skin carcinoma cells by chromosome 15 transfer or thrombospondin-1 overexpression through halted tumor vascularization.  Proc Natl Acad Sci USA. 1999;  96 2065-2070
• 5 Bolontrade M F, Stern M C, Binder R L, Zenklusen J C, Gimenez-Conti I B, Conti C J. Angiogenesis is an early event in the development of chemically induced skin tumors.  Carcinogenesis. 1998;  19 2107-2113
• 6 Bornstein P. Diversity of function is inherent in matricellular proteins: an appraisal of thrombospondin 1.  J Cell Biol. 1995;  130 503-506
• 7 Bornstein P. Thrombospondins as matricellular modulators of cell function.  J Clin Invest. 2001;  107 929-934
• 8 Bornstein P, Armstrong L C, Hankenson K D, Kyriakides T R, Yang Z. Thrombospondin 2, a matricellular protein with diverse functions.  Matrix Biol. 2000;  19 557-568
• 9 Breiteneder-Geleff S, Soleiman A, Kowalski H, Horvat R, Amann G, Kriehuber E, Diem K, Weninger W, Tschachler E, Alitalo K, Kerjaschki D. Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium.  Am J Pathol. 1999;  154 385-394
• 10 Cao Y. Endogenous angiogenesis inhibitors and their therapeutic implications.  Int J Biochem Cell Biol. 2001;  33 357-369
• 11 Carmeliet P, Jain R K. Angiogenesis in cancer and other diseases.  Nature. 2000;  407 249-257
• 12 Carreira C M, Nasser S M, di Tomaso E, Padera T P, Boucher Y, Tomarev S I, Jain R K. LYVE-1 is not restricted to the lymph vessels: expression in normal liver blood sinusoids and down-regulation in human liver cancer and cirrhosis.  Cancer Res. 2001;  61 8079-8084
• 13 Clarijs R, Ruiter D J, de Waal R M. Lymphangiogenesis in malignant tumours: Does it occur?.  J Pathol. 2001;  193 143-146
• 14 Crawford S E, Stellmach V, Murphy-Ullrich J E, Ribeiro S M, Lawler J, Hynes R O, Boivin G P, Bouck N. Thrombospondin-1 is a major activator of TGF-beta1 in vivo.  Cell. 1998;  93 1159-1170
• 15 Dameron K M, Volpert O V, Tainsky M A, Bouck N. Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1.  Science. 1994;  265 1582-1584
• 16 Davis S, Aldrich T H, Jones P F, Acheson A, Compton D L, Jain V, Ryan T E, Bruno J, Radziejewski C, Maisonpierre P C, Yancopoulos G D. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning.  Cell. 1996;  87 1161-1169
• 17 Davis S, Yancopoulos G D. The angiopoietins: Yin and Yang in angiogenesis.  Curr Top Microbiol Immunol. 1999;  237 173-185
• 18 Dawson D W, Pearce S F, Zhong R, Silverstein R L, Frazier W A, Bouck N P. CD36 mediates the In vitro inhibitory effects of thrombospondin-1 on endothelial cells.  J Cell Biol. 1997;  138 707-717
• 19 Dejana E, Corada M, Lampugnani M G. Endothelial cell- to-cell junctions.  FASEB J. 1995;  9 910-918
• 20 Dumont D J, Gradwohl G J, Fong G H, Auerbach R, Breitman M L. The endothelial-specific receptor tyrosine kinase, tek, is a member of a new subfamily of receptors.  Oncogene. 1993;  8 1293-1301
• 21 Dvorak H F, Brown L F, Detmar M, Dvorak A M. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis.  Am J Pathol. 1995;  146 1029-1039
• 22 Ferrara N. The role of vascular endothelial growth factor in pathological angiogenesis.  Breast Cancer Res Treat. 1995;  36 127-137
• 23 Filleur S, Volpert O V, Degeorges A, Voland C, Reiher F, Clezardin P, Bouck N, Cabon F. In vivo mechanisms by which tumors producing thrombospondin 1 bypass its inhibitory effects.  Genes Dev. 2001;  15 1373-1382
• 24 Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease.  Nature Med. 1995;  1 27-31
• 25 Folkman J. Angiogenesis and tumor growth.  N Engl J Med. 1996;  334 921
• 26 Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis.  Cell. 1996;  86 353-364
• 27 Hawighorst T, Oura H, Streit M, Janes L, Nguyen L, Brown L F, Oliver G, Jackson D G, Detmar M. Thrombospondin-1 selectively inhibits early- stage carcinogenesis and angiogenesis but not tumor lymphangiogenesis and lymphatic metastasis in transgenic mice.  Oncogene. 2002;  21 7945-7956
• 28 Hawighorst T, Skobe M, Streit M, Hong Y K, Velasco P, Brown L F, Riccardi L, Lange-Asschenfeldt B, Detmar M. Activation of the tie2 receptor by angiopoietin-1 enhances tumor vessel maturation and impairs squamous cell carcinoma growth.  Am J Pathol. 2002;  160 1381-1392
• 29 Hawighorst T, Velasco P, Streit M, Hong Y K, Kyriakides T, Brown L F, Bornstein P, Detmar M. Thrombospondin-2 plays a protective role in multistep carcinogenesis: a novel host anti-tumor defense mechanism.  EMBO J. 2001;  20 2631-2640
• 30 Hayes A J, Huang W Q, Yu J, Maisonpierre P C, Liu A, Kern F G, Lippman M E, McLeskey S W, Li L Y. Expression and function of angiopoietin-1 in breast cancer.  Br J Cancer. 2000;  83 1154-1160
• 31 Holash J, Maisonpierre P C, Compton D, Boland P, Alexander C R, Zagzag D, Yancopoulos G D, Wiegand S J. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF.  Science. 1999;  284 1994-1998
• 32 Holash J, Wiegand S J, Yancopoulos G D. New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF.  Oncogene. 1999;  18 5356-5362
• 33 Holmgren L, O’Reilly M S, Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression.  Nature Med.. 1995;  1 149-153
• 34 Ito N, Hasegawa R, Imaida K, Hirose M, Asamoto M, Shirai T. Concepts in multistage carcinogenesis.  Crit Rev Oncol Hematol. 1995;  21 105-133
• 35 Jackson D G, Prevo R, Clasper S, Banerji S. LYVE-1, the lymphatic system and tumor lymphangiogenesis.  Trends Immunol. 2001;  22 317-321
• 36 Jimenez B, Volpert O V, Crawford S E, Febbraio M, Silverstein R L, Bouck N. Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1.  Nature Med. 2000;  6 41-48
• 37 Kaipainen A, Korhonen J, Mustonen T, van Hinsbergh V, Fang G H, Dumont D, Breitman M, Alitalo K. Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development.  Proc Natl Acad Sci USA. 1995;  92 3566-3570
• 38 Karpanen T, Egeblad M, Karkkainen M J, Kubo H, Yla-Herttuala S, Jaattela M, Alitalo K. Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth.  Cancer Res. 2001;  61 1786-1790
• 39 Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors.  Nature Rev Cancer.. 2002;  2 727-739
• 40 Kerbel R S, Viloria P A, Okada F, Rak J. Establishing a link between oncogenes and tumor angiogenesis.  Mol Med. 1998;  4 286-295
• 41 Lawler J. The functions of thrombospondin-1 and-2.  Curr Opin Cell Biol. 2000;  12 634-640
• 42 Maisonpierre P C, Suri C, Jones P F, Bartunkova S, Wiegand S J, Radziejewski C, Compton D, McClain J, Aldrich T H, Papadopoulos N, Daly T J, Davis S, Sato T N, Yancopoulos G D. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis.  Science. 1997;  277 55-60
• 43 Mandriota S J, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R, Banerji S, Huarte J, Montesano R, Jackson D G, Orci L, Alitalo K, Christofori G, Pepper M S. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis.  Embo J. 2001;  20 672-682
• 44 Mettouchi A, Cabon F, Montreau N, Vernier P, Mercier G, Blangy D, Tricoire H, Vigier P, Binetruy B. SPARC and thrombospondin genes are repressed by the c-jun oncogene in rat embryo fibroblasts.  EMBO J. 1994;  13 5668-5678
• 45 Oliver G, Detmar M. The rediscovery of the lymphatic system: old and new insights into the development and biological function of the lymphatic vasculature.  Genes Dev. 2002;  16 773-783
• 46 Oliver G, Sosa-Pineda B, Geisendorf S, Spana E P, Doe C Q, Gruss P. Prox 1, a prospero-related homeobox gene expressed during mouse development.  Mech Dev. 1993;  44 3-16
• 47 Oshika Y, Masuda K, Tokunaga T, Hatanaka H, Kamiya T, Abe Y, Ozeki Y, Kijima H, Yamazaki H, Tamaoki N, Ueyama Y, Nakamura M. Thrombospondin 2 gene expression is correlated with decreased vascularity in non-small cell lung cancer.  Clin Cancer Res. 1998;  4 1785-1788
• 48 Paavonen K, Puolakkainen P, Jussila L, Jahkola T, Alitalo K. Vascular endothelial growth factor receptor-3 in lymphangiogenesis in wound healing.  Am J Pathol. 2000;  156 1499-1504
• 49 Pepper M S. Lymphangiogenesis and tumor metastasis: myth or reality?.  Clin Cancer Res. 2001;  7 462-468
• 50 Prevo R, Banerji S, Ferguson D J, Clasper S, Jackson D G. Mouse LYVE-1 is an endocytic receptor for hyaluronan in lymphatic endothelium.  J Biol Chem. 2001;  276 19420-19430
• 51 Rodriguez-Manzaneque J C, Lane T F, Ortega M A, Hynes R O, Lawler J, Iruela-Arispe M L. Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor.  Proc Natl Acad Sci USA. 2001;  98 12485-12390
• 52 Schultz-Cherry S, Chen H, Mosher D F, Misenheimer T M, Krutzsch H C, Roberts D D, Murphy-Ullrich J E. Regulation of transforming growth factor-beta activation by discrete sequences of thrombospondin 1.  J Biol Chem. 1995;  270 7304-7310
• 53 Skobe M, Hawighorst T, Jackson D G, Prevo R, Janes L, Velasco P, Riccardi L, Alitalo K, Claffey K, Detmar M. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis.  Nature Med. 2001;  7 192-198
• 54 Stacker S A, Achen M G, Jussila L, Baldwin M E, Alitalo K. Lymphangiogenesis and cancer metastasis.  Nature Rev Cancer. 2002;  2 573-583
• 55 Stacker S A, Caesar C, Baldwin M E, Thornton G E, Williams R A, Prevo R, Jackson D G, Nishikawa S, Kubo H, Achen M G. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics.  Nature Med. 2001;  7 186-191
• 56 Stellmach V, Volpert O V, Crawford S E, Lawler J, Hynes R O, Bouck N. Tumour suppressor genes and angiogenesis: the role of P53 in fibroblasts.  Eur J Cancer. 1996;  32 2394-2400
• 57 Streit M, Riccardi L, Velasco P, Brown L F, Hawighorst T, Bornstein P, Detmar M. Thrombospondin-2: A potent endogenous inhibitor of tumor growth and angiogenesis.  Proc Natl Acad Sci USA. 1999;  96 14888-14893
• 58 Streit M, Stephen A E, Hawighorst T, Matsuda K, Lange-Asschenfeldt B, Brown L F, Vacanti J P, Detmar M. Systemic inhibition of tumor growth and angiogenesis by thrombospondin-2 using cell-based antiangiogenic gene therapy.  Cancer Res. 2002;  62 2004-2012
• 59 Streit M, Velasco P, Brown L F, Skobe M, Richard L, Riccardi L, Lawler J, Detmar M. Overexpression of thrombospondin-1 decreases angiogenesis and inhibits the growth of human squamous cell carcinomas.  Am J Pathol. 1999;  155 441-452
• 60 Streit M, Velasco P, Riccardi L, Spencer L, Brown L F, Janes L, Lange-Asschenfeldt B, Yano K, Hawighorst T, Iruela-Arispe L ,Detmar, M. Thrombospondin-1 suppresses wound healing and granulation tissue formation in the skin of transgenic mice.  EMBO J. 2000;  19 3272-3282
• 61 Tokunaga T, Nakamura M, Oshika Y, Abe Y, Ozeki Y, Fukushima Y, Hatanaka H, Sadahiro S, Kijima H, Tsuchida T, Yamazaki H, Tamaoki N, Ueyama Y. Thrombospondin 2 expression is correlated with inhibition of angiogenesis and metastasis of colon cancer.  Br J Cancer. 1999;  79 354-359
• 62 Tolsma S S, Volpert O V, Good D J, Frazier W A, Polverini P J, Bouck N. Peptides derived from two separate domains of the matrix protein thrombospondin-1 have anti-angiogenic activity.  J Cell Biol. 1993;  122 497-511
• 63 Valtola R, Salven P, Heikkila P, Taipale J, Joensuu H, Rehn M, Pihlajaniemi T, Weich H, de Waal R, Alitalo K. VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer.  Am J Pathol. 1999;  154 1381-1390
• 64 Volpert O V, Tolsma S S, Pellerin S, Feige J J, Chen H, Mosher D F, Bouck N. Inhibition of angiogenesis by thrombospondin-2.  Biochem Biophys Res Commun. 1995;  217 326-332
• 65 Wetterwald A, Hoffstetter W, Cecchini M G, Lanske B, Wagner C, Fleisch H, Atkinson M. Characterization and cloning of the E11 antigen, a marker expressed by rat osteoblasts and osteocytes.  Bone. 1996;  18 125-132
• 66 Wigle J T, Chowdhury K, Gruss P, Oliver G. Prox1 function is crucial for mouse lens-fibre elongation.  Nature Genet. 1999;  21 318-322
• 67 Wigle J T, Harvey N, Detmar M, Lagutina I, Grosveld G, Gunn M D, Jackson D G, Oliver G. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype.  EMBO J. 2002;  21 1505-1513
• 68 Wigle J T, Oliver G. Prox1 function is required for the development of the murine lymphatic system.  Cell. 1999;  98 769-778
• 69 Yancopoulos G D, Davis S, Gale N W, Rudge J S, Wiegand S J, Holash J. Vascular-specific growth factors and blood vessel formation.  Nature. 2000;  407 242-248