- Email: [email protected]
Antiangiogenesis therapy might have the unintended effect of promoting tumor metastasis by increasing an alternative circulatory system
Medical Hypotheses 74 (2010) 360–361
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Antiangiogenesis therapy might have the unintended effect of promoting tumor metastasis by increasing an alternative circulatory system Bo Qu, Long Guo, Jinlu Ma, Yi Lv * Department of Hepatobiliary Surgery, The First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Shaanxi 710061, PR China
a r t i c l e
i n f o
Article history: Received 9 August 2009 Accepted 12 August 2009
a b s t r a c t Antiangiogenesis therapy is one of the most promising approaches to cancer treatment. Its clinical success has come out but still too limited. Vascularization of tumor is a complex and heterogenous process. So far, it has been demonstrated that several additional mechanisms can provide the tumor with oxygen and nutrients. Moreover, it is now clear that vascularization of tumor does not necessarily depend on endothelial cells proliferation and sprouting of new capillaries. Vasculogenic mimicry (VM) as an alternative circulatory system, has been described in multiple malignant tumor types, and considered to be associated with a poor prognosis for the patient. VM serves as an adjunct to the existing vasculature system, thereby aiding tumor growth as well as contributing to the metastatic process. Moreover, hypoxia has been confirmed to promote some tumor cells to form vessel-like tubes in vitro and express genes associated with VM. Yet, the current antiangiogenesis strategies, which are directed mainly against the tumor endothelium and then cause hypoxia of tumor cells, have no effect on VM. Our central hypothesis is that when the endothelium-dependent vessels are inhibited by the effective angiogenesis inhibitors, the hypoxia of tumor cells caused by antiangiogenesis may increase VM compensatively which can replace the job of endothelium-dependent vessels to maintain the tumor blood supply and provide a convenient route of tumor metastasis. As a result, antiangiogenesis therapy might have the unintended effect of promoting tumor metastasis by increasing VM. Thus, treatment strategies that target the tumor microcirculation should not only target endothelium-dependent vessels, but also take VM into account in tumors presenting VM. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Tumors can grow to a size of approximately 1–2 mm3 before their metabolic demands are restricted due to the diffusion limit of oxygen and nutrients. In order to grow beyond this size or metastasize to another organ, they must recruit new blood vessels by two processes: vasculogenesis and angiogenesis. These processes were regulated by a variety of pro- and antiangiogenic factors, and are prerequisite for further outgrowth of the tumor [1]. Current antiangiogenesis therapy is based mainly on this classic angiogenesis theory. The clinical success of current antiangiogenesis therapy has come out but still too limited [2]. Since antiangiogenesis therapy alone seems not to be sufficient to improve patient survival, clinical studies are all in combination with conventional strategies, such as chemo- and radiotherapy [2]. But their effects are still very limited. It is now clear that tumor vasculature does not necessarily depend on endothelial cell proliferation and sprouting of new capillaries. Several additional mechanisms can provide the tumor * Corresponding author. Tel.: +86 02985323626. E-mail address: [email protected] (Y. Lv). 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2009.08.020
with oxygen and nutrients [3], and the antivascular strategies are more complex than original thought.
Vasculogenic mimicry and tumor metastasis In 1999, Maniotis et al. [4] discovered a new phenomenon in the biology of tumor vascularization. Under hypoxia conditions, highly aggressive and metastatic uveal and cutaneous melanoma cells can form highly patterned vascular channels. The generation of such microvascular channels by genetically deregulated, aggressive tumor cells is termed vasculogenic mimicry (VM) to emphasize its de novo generation that is independent of angiogenesis. The channels formed by VM is composed of a basement membrane and lined by tumor cells, and no endothelial cells are found on its inner wall. Blood plasma and red blood cells can flow through the channels [5]. Tumor cells are aligned with the external superficies of the channels. VM patterns serve as an adjunct to the existing vasculature system, thereby aiding tumor growth as well as contributing to the metastatic process [6]. Furthermore, the ratio of VM surface area to the surface area of endothelial cell-lined blood vessels is much greater [7,8].
B. Qu et al. / Medical Hypotheses 74 (2010) 360–361
The unique structure of VM channels facilitates the hematogeneous metastasis of tumor cells. Tumor cells, which line in the inner surface of VM channels, are directly exposed to blood flow. Tumor cells that leak out can migrate through the bloodstream and metastasize to other organs. Furthermore, tumor cells that line the VM channels are highly malignant, poorly differentiated, and have high plasticity. These cells can degrade adjacent connective tissues and penetrate the basement membrane of blood vessels by secreting proteins that mediate tumor invasion and metastasis. Until now, VM has been described in multiple malignant tumor types and associated with a poor prognosis for the patient [9–12]. Hypothesis The current antivascular strategies are directed mainly against the tumor endothelium alone. VM has a totally different structure from endothelium-dependent vessels. Routine antiangiogenesis drugs, such as angiostatin and endostatin which are effective angiogenesis inhibitors against endothelial cells, can cause hypoxia of tumor cells, but have little effect on tumors presenting VM because of the absence of endothelial cells [13,14]. Moreover, hypoxia has been confirmed to promote some tumor cells to form vessel-like tubes in vitro and express genes associated with VM [15]. In previous experiment, we found increase of VM in an in vivo murine hepatocellular carcinoma model when treated with endostar, a popular antiangiogenesis drug. Our central hypothesis is that when the endothelium-dependent vessels are inhibited by the effective angiogenesis inhibitors and then cause hypoxia of tumor cells, VM might increase and replace the job of endothelium-dependent vessels to maintain the tumor blood supply and provide a convenient route of tumor metastasis. As a result antiangiogenesis therapy might have the unintended effect of promoting metastasis by increasing VM. So, current antiangiogenesis strategies might still leave VM and other perfusion mechanisms intact and even make them increase to compensate the tumor hypoxia, eventually result in incomplete therapy and metastasis. Future implication VM poses a major challenge to current antiangiogenesis strategies and might partly explain the reason why the clinical effect of current antiangiogenesis therapy is still too limited. Future treatment strategies targeting the tumor microcirculation should not only target endothelium-dependent vessels, but also take VM into account. So, we speculate that endothelium-targeted angiogenesis therapy in combination with VM-targeted therapy might be more effective than either of the treatments separately in tumors presenting VM. Research should focus on VM-targeted therapies to combats the recurrence and metastasis of highly malignant tumors. Recently, Mig-7 (migration-inducing protein 7), a novel human gene product, whose expression allows tumor cells to sense
361
their environment, to invade, and to form VM, has been regarded as a promising target in anti-VM therapy [16,17]. In our previous studies, the nude mice bearing a human hepatocellular carcinoma xenograft obtained longer survival time with less metastasis when treated with endostar in combination with Mig-7-specific siRNA than treated with endostar alone. In addition, the more effective approach might be based on their common target which still needs future research.
Conflicts of interest statement None declared. References [1] Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000;407(6801):249–57. [2] Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005;307(5706):58–62. [3] Hillen F, Griffioen AW. Tumour vascularization: sprouting angiogenesis and beyond. Cancer Metastasis Rev 2007. [4] Maniotis AJ, Folberg R, Hess A, et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol 1999;155(3):739–52. [5] Folberg R, Maniotis AJ. Vasculogenic mimicry. APMIS 2004;112(7–8):508–25. [6] Frenkel S, Barzel I, Levy J, et al. Demonstrating circulation in vasculogenic mimicry patterns of uveal melanoma by confocal indocyanine green angiography. Eye 2007. [7] Lin AY, Ai Z, Lee SC, et al. Comparing vasculogenic mimicry with endothelial cell-lined vessels: techniques for 3D reconstruction and quantitative analysis of tissue components from archival paraffin blocks. Appl Immunohistochem Mol Morphol 2007;15(1):113–9. [8] Chen X, Ai Z, Rasmussen M, et al. Three-dimensional reconstruction of extravascular matrix patterns and blood vessels in human uveal melanoma tissue: techniques and preliminary findings. Invest Ophthalmol Vis Sci 2003;44(7):2834–40. [9] Guzman G, Cotler SJ, Lin AY, Maniotis AJ, Folberg R. A pilot study of vasculogenic mimicry immunohistochemical expression in hepatocellular carcinoma. Arch Pathol Lab Med 2007;131(12):1776–81. [10] Zhao H, Gu XM. Study on vasculogenic mimicry in malignant esophageal stromal tumors. World J Gastroenterol 2008;14(15):2430–3. [11] Sun B, Zhang S, Zhang D, et al. Vasculogenic mimicry is associated with high tumor grade, invasion and metastasis, and short survival in patients with hepatocellular carcinoma. Oncol Rep 2006;16(4):693–8. [12] Fan YZ, Sun W, Zhang WZ, Ge CY. Vasculogenic mimicry in human primary gallbladder carcinoma and clinical significance thereof. Zhonghua Yi Xue Za Zhi 2007;87(3):145–9. [13] der Schaft DWv, Seftor RE, Seftor EA, et al. Effects of angiogenesis inhibitors on vascular network formation by human endothelial and melanoma cells. J Natl Cancer Inst 2004;96(19):1473–7. [14] Rybak SM, Sanovich E, Hollingshead MG, et al. ‘‘Vasocrine” formation of tumor cell-lined vascular spaces: implications for rational design of antiangiogenic therapies. Cancer Res 2003;63(11):2812–9. [15] der Schaft DWJv, Hillen F, Pauwels P, et al. Tumor cell plasticity in Ewing sarcoma, an alternative circulatory system stimulated by hypoxia. Cancer Res 2005;65(24):11520–8. [16] Robertson GP. Mig-7 linked to vasculogenic mimicry. Am J Pathol 2007;170(5):1454–6. [17] Petty AP, Garman KL, Winn VD, Spidel CM, Lindsey JS. Overexpression of carcinoma and embryonic cytotrophoblast cell-specific Mig-7 induces invasion and vessel-like structure formation. Am J Pathol 2007;170(5): 1763–80.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Antiangiogenesis therapy might have the unintended effect of promoting tumor metastasis by increasing an alternative circulatory system Bo Qu, Long Guo, Jinlu Ma, Yi Lv * Department of Hepatobiliary Surgery, The First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Shaanxi 710061, PR China
a r t i c l e
i n f o
Article history: Received 9 August 2009 Accepted 12 August 2009
a b s t r a c t Antiangiogenesis therapy is one of the most promising approaches to cancer treatment. Its clinical success has come out but still too limited. Vascularization of tumor is a complex and heterogenous process. So far, it has been demonstrated that several additional mechanisms can provide the tumor with oxygen and nutrients. Moreover, it is now clear that vascularization of tumor does not necessarily depend on endothelial cells proliferation and sprouting of new capillaries. Vasculogenic mimicry (VM) as an alternative circulatory system, has been described in multiple malignant tumor types, and considered to be associated with a poor prognosis for the patient. VM serves as an adjunct to the existing vasculature system, thereby aiding tumor growth as well as contributing to the metastatic process. Moreover, hypoxia has been confirmed to promote some tumor cells to form vessel-like tubes in vitro and express genes associated with VM. Yet, the current antiangiogenesis strategies, which are directed mainly against the tumor endothelium and then cause hypoxia of tumor cells, have no effect on VM. Our central hypothesis is that when the endothelium-dependent vessels are inhibited by the effective angiogenesis inhibitors, the hypoxia of tumor cells caused by antiangiogenesis may increase VM compensatively which can replace the job of endothelium-dependent vessels to maintain the tumor blood supply and provide a convenient route of tumor metastasis. As a result, antiangiogenesis therapy might have the unintended effect of promoting tumor metastasis by increasing VM. Thus, treatment strategies that target the tumor microcirculation should not only target endothelium-dependent vessels, but also take VM into account in tumors presenting VM. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Tumors can grow to a size of approximately 1–2 mm3 before their metabolic demands are restricted due to the diffusion limit of oxygen and nutrients. In order to grow beyond this size or metastasize to another organ, they must recruit new blood vessels by two processes: vasculogenesis and angiogenesis. These processes were regulated by a variety of pro- and antiangiogenic factors, and are prerequisite for further outgrowth of the tumor [1]. Current antiangiogenesis therapy is based mainly on this classic angiogenesis theory. The clinical success of current antiangiogenesis therapy has come out but still too limited [2]. Since antiangiogenesis therapy alone seems not to be sufficient to improve patient survival, clinical studies are all in combination with conventional strategies, such as chemo- and radiotherapy [2]. But their effects are still very limited. It is now clear that tumor vasculature does not necessarily depend on endothelial cell proliferation and sprouting of new capillaries. Several additional mechanisms can provide the tumor * Corresponding author. Tel.: +86 02985323626. E-mail address: [email protected] (Y. Lv). 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2009.08.020
with oxygen and nutrients [3], and the antivascular strategies are more complex than original thought.
Vasculogenic mimicry and tumor metastasis In 1999, Maniotis et al. [4] discovered a new phenomenon in the biology of tumor vascularization. Under hypoxia conditions, highly aggressive and metastatic uveal and cutaneous melanoma cells can form highly patterned vascular channels. The generation of such microvascular channels by genetically deregulated, aggressive tumor cells is termed vasculogenic mimicry (VM) to emphasize its de novo generation that is independent of angiogenesis. The channels formed by VM is composed of a basement membrane and lined by tumor cells, and no endothelial cells are found on its inner wall. Blood plasma and red blood cells can flow through the channels [5]. Tumor cells are aligned with the external superficies of the channels. VM patterns serve as an adjunct to the existing vasculature system, thereby aiding tumor growth as well as contributing to the metastatic process [6]. Furthermore, the ratio of VM surface area to the surface area of endothelial cell-lined blood vessels is much greater [7,8].
B. Qu et al. / Medical Hypotheses 74 (2010) 360–361
The unique structure of VM channels facilitates the hematogeneous metastasis of tumor cells. Tumor cells, which line in the inner surface of VM channels, are directly exposed to blood flow. Tumor cells that leak out can migrate through the bloodstream and metastasize to other organs. Furthermore, tumor cells that line the VM channels are highly malignant, poorly differentiated, and have high plasticity. These cells can degrade adjacent connective tissues and penetrate the basement membrane of blood vessels by secreting proteins that mediate tumor invasion and metastasis. Until now, VM has been described in multiple malignant tumor types and associated with a poor prognosis for the patient [9–12]. Hypothesis The current antivascular strategies are directed mainly against the tumor endothelium alone. VM has a totally different structure from endothelium-dependent vessels. Routine antiangiogenesis drugs, such as angiostatin and endostatin which are effective angiogenesis inhibitors against endothelial cells, can cause hypoxia of tumor cells, but have little effect on tumors presenting VM because of the absence of endothelial cells [13,14]. Moreover, hypoxia has been confirmed to promote some tumor cells to form vessel-like tubes in vitro and express genes associated with VM [15]. In previous experiment, we found increase of VM in an in vivo murine hepatocellular carcinoma model when treated with endostar, a popular antiangiogenesis drug. Our central hypothesis is that when the endothelium-dependent vessels are inhibited by the effective angiogenesis inhibitors and then cause hypoxia of tumor cells, VM might increase and replace the job of endothelium-dependent vessels to maintain the tumor blood supply and provide a convenient route of tumor metastasis. As a result antiangiogenesis therapy might have the unintended effect of promoting metastasis by increasing VM. So, current antiangiogenesis strategies might still leave VM and other perfusion mechanisms intact and even make them increase to compensate the tumor hypoxia, eventually result in incomplete therapy and metastasis. Future implication VM poses a major challenge to current antiangiogenesis strategies and might partly explain the reason why the clinical effect of current antiangiogenesis therapy is still too limited. Future treatment strategies targeting the tumor microcirculation should not only target endothelium-dependent vessels, but also take VM into account. So, we speculate that endothelium-targeted angiogenesis therapy in combination with VM-targeted therapy might be more effective than either of the treatments separately in tumors presenting VM. Research should focus on VM-targeted therapies to combats the recurrence and metastasis of highly malignant tumors. Recently, Mig-7 (migration-inducing protein 7), a novel human gene product, whose expression allows tumor cells to sense
361
their environment, to invade, and to form VM, has been regarded as a promising target in anti-VM therapy [16,17]. In our previous studies, the nude mice bearing a human hepatocellular carcinoma xenograft obtained longer survival time with less metastasis when treated with endostar in combination with Mig-7-specific siRNA than treated with endostar alone. In addition, the more effective approach might be based on their common target which still needs future research.
Conflicts of interest statement None declared. References [1] Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000;407(6801):249–57. [2] Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005;307(5706):58–62. [3] Hillen F, Griffioen AW. Tumour vascularization: sprouting angiogenesis and beyond. Cancer Metastasis Rev 2007. [4] Maniotis AJ, Folberg R, Hess A, et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol 1999;155(3):739–52. [5] Folberg R, Maniotis AJ. Vasculogenic mimicry. APMIS 2004;112(7–8):508–25. [6] Frenkel S, Barzel I, Levy J, et al. Demonstrating circulation in vasculogenic mimicry patterns of uveal melanoma by confocal indocyanine green angiography. Eye 2007. [7] Lin AY, Ai Z, Lee SC, et al. Comparing vasculogenic mimicry with endothelial cell-lined vessels: techniques for 3D reconstruction and quantitative analysis of tissue components from archival paraffin blocks. Appl Immunohistochem Mol Morphol 2007;15(1):113–9. [8] Chen X, Ai Z, Rasmussen M, et al. Three-dimensional reconstruction of extravascular matrix patterns and blood vessels in human uveal melanoma tissue: techniques and preliminary findings. Invest Ophthalmol Vis Sci 2003;44(7):2834–40. [9] Guzman G, Cotler SJ, Lin AY, Maniotis AJ, Folberg R. A pilot study of vasculogenic mimicry immunohistochemical expression in hepatocellular carcinoma. Arch Pathol Lab Med 2007;131(12):1776–81. [10] Zhao H, Gu XM. Study on vasculogenic mimicry in malignant esophageal stromal tumors. World J Gastroenterol 2008;14(15):2430–3. [11] Sun B, Zhang S, Zhang D, et al. Vasculogenic mimicry is associated with high tumor grade, invasion and metastasis, and short survival in patients with hepatocellular carcinoma. Oncol Rep 2006;16(4):693–8. [12] Fan YZ, Sun W, Zhang WZ, Ge CY. Vasculogenic mimicry in human primary gallbladder carcinoma and clinical significance thereof. Zhonghua Yi Xue Za Zhi 2007;87(3):145–9. [13] der Schaft DWv, Seftor RE, Seftor EA, et al. Effects of angiogenesis inhibitors on vascular network formation by human endothelial and melanoma cells. J Natl Cancer Inst 2004;96(19):1473–7. [14] Rybak SM, Sanovich E, Hollingshead MG, et al. ‘‘Vasocrine” formation of tumor cell-lined vascular spaces: implications for rational design of antiangiogenic therapies. Cancer Res 2003;63(11):2812–9. [15] der Schaft DWJv, Hillen F, Pauwels P, et al. Tumor cell plasticity in Ewing sarcoma, an alternative circulatory system stimulated by hypoxia. Cancer Res 2005;65(24):11520–8. [16] Robertson GP. Mig-7 linked to vasculogenic mimicry. Am J Pathol 2007;170(5):1454–6. [17] Petty AP, Garman KL, Winn VD, Spidel CM, Lindsey JS. Overexpression of carcinoma and embryonic cytotrophoblast cell-specific Mig-7 induces invasion and vessel-like structure formation. Am J Pathol 2007;170(5): 1763–80.