CD133 positive endothelial progenitor cells contribute to the tumour vasculature in non-small cell lung cancer

Aims: Recent results generated in a mouse model suggest that tumour angiogenesis/vasculogenesis can be initiated and maintained by bone marrow derived endothelial progenitor cells. This present study investigated the distribution and frequency of CD133 positive endothelial progenitor cells in patients with non-small cell lung cancer (NSCLC) (tumour tissue and tumour free lung regions) and healthy controls using fresh frozen specimens. The novel marker CD133 identifies human haemopoetic precursor cells, in addition to human endothelial progenitor cells. Methods: Seventy nine lung cancer specimens and 66 adjacent histologically tumour free tissues of the same patient cohort were analysed; 11 postmortem specimens from control patients who did not suffer from malignant disease served as controls. Cryostat sections were stained for CD133, CD31, vascular endothelial growth factor receptor 2 (VEGFR-2; KDR), p53, and the proliferation marker Ki-67, and the correlations were analysed. Results: Forty three of 63 evaluable tumour specimens had increased numbers of CD133 positive cells and in some cases capillary forming CD133 positive structures were detectable. In addition, 30 of 63 specimens had raised expression of KDR and 29 of 63 had increased MVD. Increased CD133 expression marginally correlated with raised KDR expression but not with p53 and Ki-67. Conclusion: A significant increase in CD133 positive cells was documented in patients with NSCLC, suggesting an involvement of endothelial progenitor cells in tumour vasculogenesis and tumour growth in these patients.

[1]  T. Schmid,et al.  Immunohistochemical typing of non-small cell lung cancer on cryostat sections: correlation with clinical parameters and prognosis , 2003, Journal of clinical pathology.

[2]  O. Kocher,et al.  Blood Markers for Vasculogenesis Increase with Tumor Progression in Patients with Breast Carcinoma , 2003, Cancer biology & therapy.

[3]  H. Dvorak Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  M. Matthay,et al.  Hypoxia upregulates VEGF expression in alveolar epithelial cells in vitro and in vivo. , 2002, American journal of physiology. Lung cellular and molecular physiology.

[5]  K. Konstantopoulos,et al.  Fluid shear- and time-dependent modulation of molecular interactions between PMNs and colon carcinomas. , 2002, American journal of physiology. Cell physiology.

[6]  G. Gastl,et al.  In vivo Release of Vascular Endothelial Growth Factor from Colorectal Carcinomas , 2002, Oncology.

[7]  W. Travis,et al.  The new World Health Organization classification of lung tumours , 2001, European Respiratory Journal.

[8]  K. Sugimachi,et al.  High vascularity in the peripheral region of non-small cell lung cancer tissue is associated with tumor progression. , 2001, Lung cancer.

[9]  S. Rafii,et al.  Impaired recruitment of bone-marrow–derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth , 2001, Nature Medicine.

[10]  G. Sledge,et al.  Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  Stanley J. Wiegand,et al.  Vascular-specific growth factors and blood vessel formation , 2000, Nature.

[12]  A. Harris,et al.  Vascular endothelial growth factor/KDR activated microvessel density versus CD31 standard microvessel density in non-small cell lung cancer. , 2000, Cancer research.

[13]  S. Dirnhofer,et al.  Evidence from a leukaemia model for maintenance of vascular endothelium by bone-marrow-derived endothelial cells , 2000, The Lancet.

[14]  S. Rafii,et al.  Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. , 2000, Blood.

[15]  K. Pantel,et al.  In vitro differentiation of endothelial cells from AC133-positive progenitor cells. , 1999, Blood.

[16]  S. Baruchel,et al.  Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. , 2000, The Journal of clinical investigation.

[17]  M. Oda,et al.  Tumor angiogenesis and recurrence in stage I non-small cell lung cancer. , 1999, The Annals of thoracic surgery.

[18]  J. Isner,et al.  Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. , 1999, Circulation research.

[19]  J. Isner,et al.  VEGF contributes to postnatal neovascularization by mobilizing bone marrow‐derived endothelial progenitor cells , 1999, The EMBO journal.

[20]  A. Giatromanolaki,et al.  Vascular endothelial growth factor, wild-type p53, and angiogenesis in early operable non-small cell lung cancer. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[21]  E. Brambilla,et al.  Lung tumors : fundamental biology and clinical management , 1998 .

[22]  J. Schnitzer Vascular targeting as a strategy for cancer therapy. , 1998, The New England journal of medicine.

[23]  C. Angeletti,et al.  Bcl2 and p53 regulate vascular endothelial growth factor (VEGF)-mediated angiogenesis in non-small cell lung carcinoma. , 1998, European journal of cancer.

[24]  J. Kearney,et al.  AC133, a novel marker for human hematopoietic stem and progenitor cells. , 1997, Blood.

[25]  M. Tsao,et al.  Angiogenesis correlates with vascular endothelial growth factor expression but not with Ki-ras oncogene activation in non-small cell lung carcinoma. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[26]  M. Buyse,et al.  Immunocytochemical markers in stage I lung cancer: relevance to prognosis. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  C. Angeletti,et al.  Angiogenesis as a prognostic indicator of survival in non-small-cell lung carcinoma: a prospective study. , 1997, Journal of the National Cancer Institute.

[28]  Takayuki Asahara,et al.  Isolation of Putative Progenitor Endothelial Cells for Angiogenesis , 1997, Science.

[29]  M. Oda,et al.  Significance of vascular endothelial growth factor messenger RNA expression in primary lung cancer. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[30]  W. Richards,et al.  Angiogenesis and molecular biologic substaging in patients with stage I non-small cell lung cancer. , 1996, The Annals of thoracic surgery.

[31]  A. Harris,et al.  Microvessel count predicts metastatic disease and survival in non‐small cell lung cancer , 1995, The Journal of pathology.

[32]  D. Harpole,et al.  A prognostic model of recurrence and death in stage I non-small cell lung cancer utilizing presentation, histopathology, and oncoprotein expression. , 1995, Cancer research.

[33]  H. DeLisser,et al.  Molecular and functional aspects of PECAM-1/CD31. , 1994, Immunology today.

[34]  K. Dameron,et al.  Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. , 1994, Science.

[35]  W. Kolch,et al.  Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. , 1994, Oncogene.

[36]  C. Angeletti,et al.  Relation of neovascularisation to metastasis of non-small-cell lung cancer , 1992, The Lancet.

[37]  D. Hanahan,et al.  Induction of angiogenesis during the transition from hyperplasia to neoplasia , 1989, Nature.