- Email: [email protected]
Angiogenesis in malignancy
Seminars in Cancer Biology 19 (2009) 277–278
Contents lists available at ScienceDirect
Seminars in Cancer Biology journal homepage: www.elsevier.com/locate/semcancer
Editorial
Angiogenesis in malignancy
Nearly 40 years ago, Dr. Judah Folkman hypothesized that all solid tumor growth is dependent on blood vessel growth and that suppression of tumor angiogenesis would be a valid approach for cancer therapy [1]. At that time, this hypothesis was not widely accepted by the medical research community and was only supported by limited experimental evidence. However, we should all thank for Dr. Folkmanˇıs scientific persistency, which eventually allows us to experience a revolution of cancer therapy using antiangiogenic and other targeted drugs. The historical overview of angiogenesis research is shown in Fig. 1. During the first two decays, angiogenesis research remained in its dormant stage. In 1994, discovery of the first endothelial cell specific endogenous inhibitor, angiostatin, by Folkman’s lab [2], was the landmark of entering the exponential growth period of angiogenesis research and triggered tremendous interests in this area. Ten years later, the first antiangiogenic cancer drug, bevacizumab (avastin), and the first antiangiogenic ocular drug, pegaptanib (macugen), for the treatment of age related macular degeneration were approved by the US FDA [3–7]. The clinical success of using antiangiogenic agents for the treatment cancer and non-malignant diseases sets the historical milestone of antiangiogenic therapy and provides the conclusive proof of Judah Folkmanˇıs idea. Today, several antiangiogenic drugs including bevacizumab, sunitinib, and sorafenib are routinely used as an essential component of the first-line regimen for treatment of various human cancers [8,9]. However, current antiangiogenic drugs for cancer therapy are far from optimal and produce only minor beneficial effects with exceptions of renal cell carcinoma and ovarian cancer [8]. In some other types of cancers such as pancreatic cancer antiangiogenic monotherapy or combinations with chemotherapy has not shown significant clinical benefits [10,11]. It is not known why various tumor types differentially response to antiangiogenic therapy. Both clinical and experimental experiences demonstrate that antiangogenic drugs may develop unconventional drug resistance [12]. The molecular mechanisms underlying drug resistance remain complex and uncharacterized. With limited clinical experiences, we are facing tremendous difficulties in exploring many unknown territories in cancer therapy. For example, recent studies in mouse tumor models show that antiangiogenic drugs can even promote cancer cell invasion and metastasis [13,14]. If so, those majority patients who do not benefit from antiangiogenic therapy might take a high risk to accelerate metastatic spread. How long time should the cancer patients receive antiangiogenic therapy? According to preclinical findings, break in proceedings of antiangiogenic therapy could produce rebound and rigorous tumor revasculariza1044-579X/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.semcancer.2009.11.001
tion within a relatively short time [15,16]. If the same angiogenic rebound effect also exists during clinical practice, cancer patients should receive antiangiogenic therapy for the rest of their lives. Can they economically afford to use these expensive drugs for the rest of life? If long-term therapy is considered, what are the reverse effects? Recent findings show that the survival benefit of antiangiogenic agents can be uncoupled from their inhibitory effects on tumor size, suggesting that the therapeutic target might be located outside of tumor [17]. In experimental tumor models, therapeutic benefits of anti-VEGF drugs have significantly been correlated with improvement of systemic cancer syndrome. Similarly, tumor size is not a reliable surrogate marker for predicting clinical benefit and patient morbidity in association with antiangiogenic drugs [18]. In addition to hemangiogenesis, most known angiogenic factors including VEGF-A, VEGF-C, PDGF-B, HGF, IGF and angiopoietins are able to induce lymphangiogenesis, which is essential lymphatic metastasis [19–27]. Currently, it is unclear if the available antiangiogenic drugs would be able to prevent or inhibit lymphatic metastasis. If so, these anti-metastatic effects would be in a paradox to stimulation of metastasis by antiangiogenic drugs seen in mouse models. These controversial issues warrant further investigation by understanding molecular mechanisms of basic biology. Although we are still at the early stage of clinical practice and optimization of antiangiogenic therapy, the initial success with this class of drugs in cancer therapy reflects positive signals that we are heading toward the correct direction. With many bulks of diversified antiangiogenic agents available in the near future, we are expecting some exciting achievements of antiangiogenic cancer therapy, which may eventually lead to successful treatment of malignancy as manageable disease. This special issue highlights both basic and clinical advances of angiogenesis research in the oncology area. These include mechanisms of tumor angiogenesis, functions of extracellular matrix, endogenous angiogenesis inhibitors, lymphangiogenesis, animal models of tumor angiogenesis, and clinical aspects of antiangiogenic drugs. I thank all authors and distinguished experts in the tumor angiogenesis field to contribute different chapters of this issue. Regrettably, owing to a limited number of articles published in each issue of Seminars in Cancer Biology, we are not able to cover all aspects of tumor angiogenesis and therapy. On behalf of all authors, I would like to thank Dr. Eva Klein for giving us this opportunity to guest-edit this special issue of Seminars in Cancer Biology. We thank Dr. Eva Klein and Dr. George Klein for their immense interests and inspiring visions in tumor angiogenesis research and therapy.
278
Editorial / Seminars in Cancer Biology 19 (2009) 277–278
Fig. 1. Historical overview of publications in angiogenesis research. Dr. Judah Folkmanˇıs single hypothetic paper published in 1971 [1] laid the first cornerstone of angiogenesis research. Unfortunately, this research field remained in its dormant stage for approximately next 20 years. The discovery of angiostatin in 1994 triggered the exponential growth phase of this research area. The success of the first two antiangiogenic drugs for the treatment of human cancer and macular degeneration are the significant milestones for further clinical development of antiangiogenic drugs. Now, we are experiencing the most exciting time in novel targeted therapies against malignant and nonmalignant diseases. Publication numbers simply reflect the growth rate of the angiogenesis research, which becomes explosive during the last decade. It is predicted that publication numbers will continue to rise and probably angiogenesis research will be one of the most important field in biomedical research.
References [1] Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285(21):1182–6. [2] O’Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994;79(2):315–28. [3] Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350(23):2335–42. [4] Mayer RJ. Two steps forward in the treatment of colorectal cancer. N Engl J Med 2004;350(23):2406–8. [5] Sharieff W. Bevacizumab in colorectal cancer. N Engl J Med 2004;351(16):1690–1, author reply 1690–1. [6] Sonpavde G. Bevacizumab in colorectal cancer. N Engl J Med 2004;351(16):1690–1, author reply 1690–1. [7] Gragoudas ES, Adamis AP, Cunningham Jr ET, Feinsod M, Guyer DR. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004;351(27):2805–16. [8] Kerbel RS. Tumor angiogenesis. N Engl J Med 2008;358(19):2039–49. [9] Cao Y. Molecular mechanisms and therapeutic development of angiogenesis inhibitors. Adv Cancer Res 2008;100:113–31. [10] Kindler HL, Friberg G, Singh DA, Locker G, Nattam S, Kozloff M, et al. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 2005;23(31):8033–40. [11] Kulke MH, Lenz HJ, Meropol NJ, Posey J, Ryan DP, Picus J, et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 2008;26(20):3403–10. [12] Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 2008;8(8):592–603. [13] Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 2009;15(3):232–9. [14] Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, Inoue M, Bergers G, Hanahan D, Casanovas O. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009;15(3):220–31. [15] Loupakis F, Falcone A, Masi G, Fioravanti A, Kerbel RS, Del Tacca M, Bocci G. Vascular endothelial growth factor levels in immunodepleted plasma of cancer patients as a possible pharmacodynamic marker for bevacizumab activity. J Clin Oncol 2007;25(13):1816–8.
[16] Mancuso MR, Davis R, Norberg SM, O’Brien S, Sennino B, Nakahara T, et al. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest 2006;116(10):2610–21. [17] Xue Y, Religa P, Cao R, Hansen AJ, Lucchini F, Jones B, et al. Anti-VEGF agents confer survival advantages to tumor-bearing mice by improving cancerassociated systemic syndrome. Proc Natl Acad Sci USA 2008;105(47):18513– 8. [18] Ledford H. Drug markers questioned. Nature 2008;452(7187):510–1. [19] Bjorndahl MA, Cao R, Burton JB, Brakenhielm E, Religa P, Galter D, Wu L, Cao Y. Vascular endothelial growth factor-a promotes peritumoral lymphangiogenesis and lymphatic metastasis. Cancer Res 2005;65(20):9261–8. [20] Cao R, Bjorndahl MA, Religa P, Clasper S, Garvin S, Galter D, et al. PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell 2004;6(4):333–45. [21] Bjorndahl M, Cao R, Nissen LJ, Clasper S, Johnson LA, Xue Y, et al. Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo. Proc Natl Acad Sci USA 2005;102(43):15593–8. [22] Cao R, Bjorndahl MA, Gallego MI, Chen S, Religa P, Hansen AJ, et al. Hepatocyte growth factor is a lymphangiogenic factor with an indirect mechanism of action. Blood 2006;107(9):3531–6. [23] Jiang WG, Davies G, Martin TA, Parr C, Watkins G, Mansel RE, et al. The potential lymphangiogenic effects of hepatocyte growth factor/scatter factor in vitro and in vivo. Int J Mol Med 2005;16(4):723–8. [24] Kajiya K, Hirakawa S, Ma B, Drinnenberg I, Detmar M. Hepatocyte growth factor promotes lymphatic vessel formation and function. EMBO J 2005;24(16):2885–95. [25] Morisada T, Oike Y, Yamada Y, Urano T, Akao M, Kubota Y, et al. Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation. Blood 2005;105(12):4649–56. [26] Partanen TA, Paavonen K. Lymphatic versus blood vascular endothelial growth factors and receptors in humans. Microsc Res Tech 2001;55(2):108– 21. [27] Veikkola T, Alitalo K. Dual role of Ang2 in postnatal angiogenesis and lymphangiogenesis. Dev Cell 2002;3(3):302–4.
Yihai Cao Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Nobelsvag 16, 171 77, Stockholm, Sweden E-mail address: [email protected]
Contents lists available at ScienceDirect
Seminars in Cancer Biology journal homepage: www.elsevier.com/locate/semcancer
Editorial
Angiogenesis in malignancy
Nearly 40 years ago, Dr. Judah Folkman hypothesized that all solid tumor growth is dependent on blood vessel growth and that suppression of tumor angiogenesis would be a valid approach for cancer therapy [1]. At that time, this hypothesis was not widely accepted by the medical research community and was only supported by limited experimental evidence. However, we should all thank for Dr. Folkmanˇıs scientific persistency, which eventually allows us to experience a revolution of cancer therapy using antiangiogenic and other targeted drugs. The historical overview of angiogenesis research is shown in Fig. 1. During the first two decays, angiogenesis research remained in its dormant stage. In 1994, discovery of the first endothelial cell specific endogenous inhibitor, angiostatin, by Folkman’s lab [2], was the landmark of entering the exponential growth period of angiogenesis research and triggered tremendous interests in this area. Ten years later, the first antiangiogenic cancer drug, bevacizumab (avastin), and the first antiangiogenic ocular drug, pegaptanib (macugen), for the treatment of age related macular degeneration were approved by the US FDA [3–7]. The clinical success of using antiangiogenic agents for the treatment cancer and non-malignant diseases sets the historical milestone of antiangiogenic therapy and provides the conclusive proof of Judah Folkmanˇıs idea. Today, several antiangiogenic drugs including bevacizumab, sunitinib, and sorafenib are routinely used as an essential component of the first-line regimen for treatment of various human cancers [8,9]. However, current antiangiogenic drugs for cancer therapy are far from optimal and produce only minor beneficial effects with exceptions of renal cell carcinoma and ovarian cancer [8]. In some other types of cancers such as pancreatic cancer antiangiogenic monotherapy or combinations with chemotherapy has not shown significant clinical benefits [10,11]. It is not known why various tumor types differentially response to antiangiogenic therapy. Both clinical and experimental experiences demonstrate that antiangogenic drugs may develop unconventional drug resistance [12]. The molecular mechanisms underlying drug resistance remain complex and uncharacterized. With limited clinical experiences, we are facing tremendous difficulties in exploring many unknown territories in cancer therapy. For example, recent studies in mouse tumor models show that antiangiogenic drugs can even promote cancer cell invasion and metastasis [13,14]. If so, those majority patients who do not benefit from antiangiogenic therapy might take a high risk to accelerate metastatic spread. How long time should the cancer patients receive antiangiogenic therapy? According to preclinical findings, break in proceedings of antiangiogenic therapy could produce rebound and rigorous tumor revasculariza1044-579X/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.semcancer.2009.11.001
tion within a relatively short time [15,16]. If the same angiogenic rebound effect also exists during clinical practice, cancer patients should receive antiangiogenic therapy for the rest of their lives. Can they economically afford to use these expensive drugs for the rest of life? If long-term therapy is considered, what are the reverse effects? Recent findings show that the survival benefit of antiangiogenic agents can be uncoupled from their inhibitory effects on tumor size, suggesting that the therapeutic target might be located outside of tumor [17]. In experimental tumor models, therapeutic benefits of anti-VEGF drugs have significantly been correlated with improvement of systemic cancer syndrome. Similarly, tumor size is not a reliable surrogate marker for predicting clinical benefit and patient morbidity in association with antiangiogenic drugs [18]. In addition to hemangiogenesis, most known angiogenic factors including VEGF-A, VEGF-C, PDGF-B, HGF, IGF and angiopoietins are able to induce lymphangiogenesis, which is essential lymphatic metastasis [19–27]. Currently, it is unclear if the available antiangiogenic drugs would be able to prevent or inhibit lymphatic metastasis. If so, these anti-metastatic effects would be in a paradox to stimulation of metastasis by antiangiogenic drugs seen in mouse models. These controversial issues warrant further investigation by understanding molecular mechanisms of basic biology. Although we are still at the early stage of clinical practice and optimization of antiangiogenic therapy, the initial success with this class of drugs in cancer therapy reflects positive signals that we are heading toward the correct direction. With many bulks of diversified antiangiogenic agents available in the near future, we are expecting some exciting achievements of antiangiogenic cancer therapy, which may eventually lead to successful treatment of malignancy as manageable disease. This special issue highlights both basic and clinical advances of angiogenesis research in the oncology area. These include mechanisms of tumor angiogenesis, functions of extracellular matrix, endogenous angiogenesis inhibitors, lymphangiogenesis, animal models of tumor angiogenesis, and clinical aspects of antiangiogenic drugs. I thank all authors and distinguished experts in the tumor angiogenesis field to contribute different chapters of this issue. Regrettably, owing to a limited number of articles published in each issue of Seminars in Cancer Biology, we are not able to cover all aspects of tumor angiogenesis and therapy. On behalf of all authors, I would like to thank Dr. Eva Klein for giving us this opportunity to guest-edit this special issue of Seminars in Cancer Biology. We thank Dr. Eva Klein and Dr. George Klein for their immense interests and inspiring visions in tumor angiogenesis research and therapy.
278
Editorial / Seminars in Cancer Biology 19 (2009) 277–278
Fig. 1. Historical overview of publications in angiogenesis research. Dr. Judah Folkmanˇıs single hypothetic paper published in 1971 [1] laid the first cornerstone of angiogenesis research. Unfortunately, this research field remained in its dormant stage for approximately next 20 years. The discovery of angiostatin in 1994 triggered the exponential growth phase of this research area. The success of the first two antiangiogenic drugs for the treatment of human cancer and macular degeneration are the significant milestones for further clinical development of antiangiogenic drugs. Now, we are experiencing the most exciting time in novel targeted therapies against malignant and nonmalignant diseases. Publication numbers simply reflect the growth rate of the angiogenesis research, which becomes explosive during the last decade. It is predicted that publication numbers will continue to rise and probably angiogenesis research will be one of the most important field in biomedical research.
References [1] Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285(21):1182–6. [2] O’Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994;79(2):315–28. [3] Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350(23):2335–42. [4] Mayer RJ. Two steps forward in the treatment of colorectal cancer. N Engl J Med 2004;350(23):2406–8. [5] Sharieff W. Bevacizumab in colorectal cancer. N Engl J Med 2004;351(16):1690–1, author reply 1690–1. [6] Sonpavde G. Bevacizumab in colorectal cancer. N Engl J Med 2004;351(16):1690–1, author reply 1690–1. [7] Gragoudas ES, Adamis AP, Cunningham Jr ET, Feinsod M, Guyer DR. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004;351(27):2805–16. [8] Kerbel RS. Tumor angiogenesis. N Engl J Med 2008;358(19):2039–49. [9] Cao Y. Molecular mechanisms and therapeutic development of angiogenesis inhibitors. Adv Cancer Res 2008;100:113–31. [10] Kindler HL, Friberg G, Singh DA, Locker G, Nattam S, Kozloff M, et al. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 2005;23(31):8033–40. [11] Kulke MH, Lenz HJ, Meropol NJ, Posey J, Ryan DP, Picus J, et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 2008;26(20):3403–10. [12] Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 2008;8(8):592–603. [13] Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 2009;15(3):232–9. [14] Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, Inoue M, Bergers G, Hanahan D, Casanovas O. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009;15(3):220–31. [15] Loupakis F, Falcone A, Masi G, Fioravanti A, Kerbel RS, Del Tacca M, Bocci G. Vascular endothelial growth factor levels in immunodepleted plasma of cancer patients as a possible pharmacodynamic marker for bevacizumab activity. J Clin Oncol 2007;25(13):1816–8.
[16] Mancuso MR, Davis R, Norberg SM, O’Brien S, Sennino B, Nakahara T, et al. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest 2006;116(10):2610–21. [17] Xue Y, Religa P, Cao R, Hansen AJ, Lucchini F, Jones B, et al. Anti-VEGF agents confer survival advantages to tumor-bearing mice by improving cancerassociated systemic syndrome. Proc Natl Acad Sci USA 2008;105(47):18513– 8. [18] Ledford H. Drug markers questioned. Nature 2008;452(7187):510–1. [19] Bjorndahl MA, Cao R, Burton JB, Brakenhielm E, Religa P, Galter D, Wu L, Cao Y. Vascular endothelial growth factor-a promotes peritumoral lymphangiogenesis and lymphatic metastasis. Cancer Res 2005;65(20):9261–8. [20] Cao R, Bjorndahl MA, Religa P, Clasper S, Garvin S, Galter D, et al. PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell 2004;6(4):333–45. [21] Bjorndahl M, Cao R, Nissen LJ, Clasper S, Johnson LA, Xue Y, et al. Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo. Proc Natl Acad Sci USA 2005;102(43):15593–8. [22] Cao R, Bjorndahl MA, Gallego MI, Chen S, Religa P, Hansen AJ, et al. Hepatocyte growth factor is a lymphangiogenic factor with an indirect mechanism of action. Blood 2006;107(9):3531–6. [23] Jiang WG, Davies G, Martin TA, Parr C, Watkins G, Mansel RE, et al. The potential lymphangiogenic effects of hepatocyte growth factor/scatter factor in vitro and in vivo. Int J Mol Med 2005;16(4):723–8. [24] Kajiya K, Hirakawa S, Ma B, Drinnenberg I, Detmar M. Hepatocyte growth factor promotes lymphatic vessel formation and function. EMBO J 2005;24(16):2885–95. [25] Morisada T, Oike Y, Yamada Y, Urano T, Akao M, Kubota Y, et al. Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation. Blood 2005;105(12):4649–56. [26] Partanen TA, Paavonen K. Lymphatic versus blood vascular endothelial growth factors and receptors in humans. Microsc Res Tech 2001;55(2):108– 21. [27] Veikkola T, Alitalo K. Dual role of Ang2 in postnatal angiogenesis and lymphangiogenesis. Dev Cell 2002;3(3):302–4.
Yihai Cao Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Nobelsvag 16, 171 77, Stockholm, Sweden E-mail address: [email protected]