HER2 Support Group Forums - View Single Post - BPH-715 (revised Zoledronate) A New Weapon Against Tumor Cells

Rich66 · 11-17-2009, 04:27 PM

Cancer Res. 2009 Sep 15;69(18):7243-51. Epub 2009 Sep 8.
Glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via vascular endothelial growth factor and stromal-derived factor 1.

Folkins C, Shaked Y, Man S, Tang T, Lee CR, Zhu Z, Hoffman RM, Kerbel RS.
Department of Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
Cancer stem cells (CSC) are predicted to be critical drivers of tumor progression due to their self-renewal capacity and limitless proliferative potential. An emerging area of research suggests that CSC may also support tumor progression by promoting tumor angiogenesis. To investigate how CSC contribute to tumor vascular development, we used an approach comparing tumor xenografts of the C6 glioma cell line containing either a low or a high fraction of CSC. Compared with CSC-low tumors, CSC-high tumors exhibited increased microvessel density and blood perfusion and induced increased mobilization and tumor recruitment of bone marrow-derived endothelial progenitor cells (EPC). CSC-high C6 cell cultures also induced higher levels of endothelial cell proliferation and tubule organization in vitro compared with CSC-low cultures. CSC-high cultures and tumors expressed increased levels of the proangiogenic factors vascular endothelial growth factor and stromal-derived factor 1, and when signaling by either factor was blocked, all aspects of angiogenesis observed in CSC-high cultures and tumors, including microvessel density, perfusion, EPC mobilization/recruitment, and stimulation of endothelial cell activity, were reduced to levels comparable with those observed in CSC-low cultures/tumors. These results suggest that CSC contribute to tumor angiogenesis by promoting both local endothelial cell activity and systemic angiogenic processes involving bone marrow-derived EPC in a vascular endothelial growth factor-dependent and stromal-derived factor 1-dependent manner.

PMID: 19738068 [PubMed - indexed for MEDLINE]

Biochim Biophys Acta. 2009 Aug;1796(1):33-40. Epub 2009 May 19.
Bone marrow-derived endothelial progenitor cells contribute to the angiogenic switch in tumor growth and metastatic progression.

Gao D, Nolan D, McDonnell K, Vahdat L, Benezra R, Altorki N, Mittal V.
Department of Cardiothoracic Surgery, Lehman Brothers Lung Cancer Research Center, Cornell University Medical Center, New York, NY 10065, USA.
Emerging evidence indicates that bone marrow (BM)-derived endothelial progenitor cells (EPCs) contribute to angiogenesis-mediated growth of certain tumors in mice and human. EPCs regulate the angiogenic switch via paracrine secretion of proangiogenic growth factors and by direct luminal incorporation into sprouting nascent vessels. While the contributions of EPCs to neovessel formation in spontaneous and transplanted tumors and to the metastatic transition have been reported to be relatively low, remarkably, specific EPC ablation in vivo has resulted in severe angiogenesis inhibition and impaired primary and metastatic tumor growth. The existence of a BM reservoir of EPCs, and the selective involvement of EPCs in neovascularization, have attracted considerable interest because these cells represent novel target for therapeutic intervention. In addition, EPCs are also being used as pharmacodynamic surrogate markers for monitoring cancer progression, as well as for optimizing efficacy of anti-angiogenic therapies in the clinic. This review will focus primarily on recent advances and emerging concepts in the field of EPC biology and discuss ongoing debates involving the role of EPCs in tumor neovascularization. For detailed information on the in vitro characterization of EPCs contribution to non-tumor pathologies, the reader is directed towards several excellent reviews and publications [F. Bertolini, Y. Shaked, P. Mancuso and R.S. Kerbel, Nat. Rev., Cancer 6 (2006) 835-845. [1]] [J.M. Hill, T. Finkel and A.A. Quyyumi, Vox Sang. 87 Suppl 2 (2004) 31-37. [2]] [A.Y. Khakoo and T. Finkel, Annu. Rev. Med. 56 (2005) 79-101. [3]] [H.G. Kopp, C.A. Ramos and S. Rafii, Curr. Opin. Hematol. 13 (2006) 175-181. [4]; K.K. Hirschi, D.A. Ingram and M.C. Yoder, Arterioscler. Thromb. Vasc. Biol. 28 (2008) 1584-1595. [5]; F. Timmermans, J. Plum, M.C. Yoder, D.A. Ingram, B. Vandekerckhove and J. Case, J. Cell. Mol. Med. 13 (2009) 87-102. [6]] and reviews by Bertolini, Voest and Yoder in this issue.

PMID: 19460418 [PubMed - indexed for MEDLINE]

Int J Cancer. 2009 Oct 15;125(8):1771-7.
Endothelial progenitor cells do not contribute to tumor endothelium in primary and metastatic tumors.

Wickersheim A, Kerber M, de Miguel LS, Plate KH, Machein MR.
Tumor Angiogenesis Research Group, Department of Neurosurgery, University of Freiburg Medical School, D-79106 Freiburg, Germany.
Despite extensive research, the contribution of bone-marrow-derived endothelial progenitor cells (BM-EPC) to tumor angiogenesis remains controversial. In previous publications, the extent of incorporation of BM-EPCs into the endothelial cell (EC) layer in different tumor models has been reported as significant in some studies but undetectable in others. Here, we studied the differentiation of BM-EPCs and its contribution to tumor vessels in experimental and spontaneous lung metastasis (B16 melanoma and prostate carcinoma), in an autochthonous transgenic model of prostate tumorigenesis, in orthotopically implanted lung tumors [Lewis lung carcinoma (LLC)], in heterotopic subcutaneous models (LLC and C1 prostate carcinoma) growing in green fluorescent protein (GFP)-expressing bone marrow (BM) chimeras. Immunofluorescence was performed with a set of endothelial and hematopoietic markers and confocal microscopy was used to generate 3D reconstruction images. By performing rigorously conducted morphological studies, we found no evidence of BM-EPCs differentiation into tumor endothelium independently of tumor type, grade and organ site in primary and metastatic tumors. The vast majority of GFP(+) cells were trafficking leucocytes or periendothelial myeloid cells. To explore the possibility that local overexpression of vascular endothelial growth factor (VEGF) might increase the numbers of incorporated BM-EPCs, we analyzed tumors genetically manipulated to overexpress VEGF(164). Local VEGF production induces a massive infiltration of bone-marrow-derived cells, but did not lead to vessel wall integration of these cells. Collectively, these findings suggest that during tumor progression vascularization occurs primarily via classical tumor angiogenesis (e.g., sprouting of pre-existing ECs), whereas BM-EPCs do not incorporate into the vessel wall to any significant extent.

PMID: 19582874 [PubMed - indexed for MEDLINE]

11-17-2009, 04:27 PM	#28
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Re: BPH-715 (revised Zoledronate) A New Weapon Against Tumor Cells Cancer Res. 2009 Sep 15;69(18):7243-51. Epub 2009 Sep 8. Glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via vascular endothelial growth factor and stromal-derived factor 1. Folkins C, Shaked Y, Man S, Tang T, Lee CR, Zhu Z, Hoffman RM, Kerbel RS. Department of Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada. Cancer stem cells (CSC) are predicted to be critical drivers of tumor progression due to their self-renewal capacity and limitless proliferative potential. An emerging area of research suggests that CSC may also support tumor progression by promoting tumor angiogenesis. To investigate how CSC contribute to tumor vascular development, we used an approach comparing tumor xenografts of the C6 glioma cell line containing either a low or a high fraction of CSC. Compared with CSC-low tumors, CSC-high tumors exhibited increased microvessel density and blood perfusion and induced increased mobilization and tumor recruitment of bone marrow-derived endothelial progenitor cells (EPC). CSC-high C6 cell cultures also induced higher levels of endothelial cell proliferation and tubule organization in vitro compared with CSC-low cultures. CSC-high cultures and tumors expressed increased levels of the proangiogenic factors vascular endothelial growth factor and stromal-derived factor 1, and when signaling by either factor was blocked, all aspects of angiogenesis observed in CSC-high cultures and tumors, including microvessel density, perfusion, EPC mobilization/recruitment, and stimulation of endothelial cell activity, were reduced to levels comparable with those observed in CSC-low cultures/tumors. These results suggest that CSC contribute to tumor angiogenesis by promoting both local endothelial cell activity and systemic angiogenic processes involving bone marrow-derived EPC in a vascular endothelial growth factor-dependent and stromal-derived factor 1-dependent manner. PMID: 19738068 [PubMed - indexed for MEDLINE] Biochim Biophys Acta. 2009 Aug;1796(1):33-40. Epub 2009 May 19. Bone marrow-derived endothelial progenitor cells contribute to the angiogenic switch in tumor growth and metastatic progression. Gao D, Nolan D, McDonnell K, Vahdat L, Benezra R, Altorki N, Mittal V. Department of Cardiothoracic Surgery, Lehman Brothers Lung Cancer Research Center, Cornell University Medical Center, New York, NY 10065, USA. Emerging evidence indicates that bone marrow (BM)-derived endothelial progenitor cells (EPCs) contribute to angiogenesis-mediated growth of certain tumors in mice and human. EPCs regulate the angiogenic switch via paracrine secretion of proangiogenic growth factors and by direct luminal incorporation into sprouting nascent vessels. While the contributions of EPCs to neovessel formation in spontaneous and transplanted tumors and to the metastatic transition have been reported to be relatively low, remarkably, specific EPC ablation in vivo has resulted in severe angiogenesis inhibition and impaired primary and metastatic tumor growth. The existence of a BM reservoir of EPCs, and the selective involvement of EPCs in neovascularization, have attracted considerable interest because these cells represent novel target for therapeutic intervention. In addition, EPCs are also being used as pharmacodynamic surrogate markers for monitoring cancer progression, as well as for optimizing efficacy of anti-angiogenic therapies in the clinic. This review will focus primarily on recent advances and emerging concepts in the field of EPC biology and discuss ongoing debates involving the role of EPCs in tumor neovascularization. For detailed information on the in vitro characterization of EPCs contribution to non-tumor pathologies, the reader is directed towards several excellent reviews and publications [F. Bertolini, Y. Shaked, P. Mancuso and R.S. Kerbel, Nat. Rev., Cancer 6 (2006) 835-845. [1]] [J.M. Hill, T. Finkel and A.A. Quyyumi, Vox Sang. 87 Suppl 2 (2004) 31-37. [2]] [A.Y. Khakoo and T. Finkel, Annu. Rev. Med. 56 (2005) 79-101. [3]] [H.G. Kopp, C.A. Ramos and S. Rafii, Curr. Opin. Hematol. 13 (2006) 175-181. [4]; K.K. Hirschi, D.A. Ingram and M.C. Yoder, Arterioscler. Thromb. Vasc. Biol. 28 (2008) 1584-1595. [5]; F. Timmermans, J. Plum, M.C. Yoder, D.A. Ingram, B. Vandekerckhove and J. Case, J. Cell. Mol. Med. 13 (2009) 87-102. [6]] and reviews by Bertolini, Voest and Yoder in this issue. PMID: 19460418 [PubMed - indexed for MEDLINE] Int J Cancer. 2009 Oct 15;125(8):1771-7. Endothelial progenitor cells do not contribute to tumor endothelium in primary and metastatic tumors. Wickersheim A, Kerber M, de Miguel LS, Plate KH, Machein MR. Tumor Angiogenesis Research Group, Department of Neurosurgery, University of Freiburg Medical School, D-79106 Freiburg, Germany. Despite extensive research, the contribution of bone-marrow-derived endothelial progenitor cells (BM-EPC) to tumor angiogenesis remains controversial. In previous publications, the extent of incorporation of BM-EPCs into the endothelial cell (EC) layer in different tumor models has been reported as significant in some studies but undetectable in others. Here, we studied the differentiation of BM-EPCs and its contribution to tumor vessels in experimental and spontaneous lung metastasis (B16 melanoma and prostate carcinoma), in an autochthonous transgenic model of prostate tumorigenesis, in orthotopically implanted lung tumors [Lewis lung carcinoma (LLC)], in heterotopic subcutaneous models (LLC and C1 prostate carcinoma) growing in green fluorescent protein (GFP)-expressing bone marrow (BM) chimeras. Immunofluorescence was performed with a set of endothelial and hematopoietic markers and confocal microscopy was used to generate 3D reconstruction images. By performing rigorously conducted morphological studies, we found no evidence of BM-EPCs differentiation into tumor endothelium independently of tumor type, grade and organ site in primary and metastatic tumors. The vast majority of GFP(+) cells were trafficking leucocytes or periendothelial myeloid cells. To explore the possibility that local overexpression of vascular endothelial growth factor (VEGF) might increase the numbers of incorporated BM-EPCs, we analyzed tumors genetically manipulated to overexpress VEGF(164). Local VEGF production induces a massive infiltration of bone-marrow-derived cells, but did not lead to vessel wall integration of these cells. Collectively, these findings suggest that during tumor progression vascularization occurs primarily via classical tumor angiogenesis (e.g., sprouting of pre-existing ECs), whereas BM-EPCs do not incorporate into the vessel wall to any significant extent. PMID: 19582874 [PubMed - indexed for MEDLINE] __________________ Mom's treatment history (link)