scholarly journals Establishment of a Pre-vascularized 3D Lung Cancer Model in Fibrin Gel—Influence of Hypoxia and Cancer-Specific Therapeutics

Author(s):  
Caroline Kniebs ◽  
Anja Elisabeth Luengen ◽  
Daniel Guenther ◽  
Christian Gabriel Cornelissen ◽  
Thomas Schmitz-Rode ◽  
...  

Lung cancer is the most frequently diagnosed cancer worldwide and the one that causes the highest mortality. In order to understand the disease and to develop new treatments, in vitro human lung cancer model systems which imitate the physiological conditions is of high significance. In this study, a human 3D lung cancer model was established that features the organization of a tumor with focus on tumor angiogenesis. Vascular networks were formed by co-culture of human umbilical vein endothelial cells and adipose tissue-derived mesenchymal stem cells (ASC) for 14 days in fibrin. A part of the pre-vascularized fibrin gel was replaced by fibrin gel containing lung cancer cells (A549) to form tri-cultures. This 3D cancer model system was cultured under different culture conditions and its behaviour after treatment with different concentrations of tumor-specific therapeutics was evaluated. The evaluation was performed by measurement of metabolic activity, viability, quantification of two-photon laser scanning microscopy and measurement of the proangiogenic factor vascular endothelial growth factor in the supernatant. Hypoxic conditions promoted vascularization compared to normoxic cultured controls in co- and tri-cultures as shown by significantly increased vascular structures, longer structures with a higher area and volume, and secretion of vascular endothelial growth factor. Cancer cells also promoted vascularization. Treatment with 50 µM gefitinib or 50 nM paclitaxel decreased the vascularization significantly. VEGF secretion was only reduced after treatment with gefitinib, while in contrast secretion remained constant during medication with paclitaxel. The findings suggest that the herein described 3D lung cancer model provides a novel platform to investigate the angiogenic potential of cancer cells and its responses to therapeutics. Thus, it can serve as a promising approach for the development and patient-specific pre-selection of anticancer treatment.

Blood ◽  
2011 ◽  
Vol 118 (9) ◽  
pp. 2622-2631 ◽  
Author(s):  
Jai-Hyun Kim ◽  
Dong Soon Choi ◽  
Ok-Hee Lee ◽  
Seung-Hyun Oh ◽  
Scott M. Lippman ◽  
...  

Abstract Most antiangiogenic therapies currently being evaluated in clinical trials target the vascular endothelial growth factor pathway; however, the tumor vasculature can acquire resistance to vascular endothelial growth factor-targeted therapy by shifting to other angiogenesis mechanisms. Insulin-like growth factor binding protein-3 (IGFBP-3) has been reported to suppress tumor growth and angiogenesis by both IGF-dependent and IGF-independent mechanisms; however, understanding of its IGF-independent mechanisms is limited. We observed that IGFBP-3 blocked tumor angiogenesis and growth in non–small cell lung cancer and head and neck squamous cell carcinoma. Conditioned media from an IGFBP-3–treated non–small cell lung cancer cell line displayed a significantly decreased capacity to induce HUVEC proliferation and aortic sprouting. In cancer cells, IGFBP-3 directly interacted with Erk1/2, leading to inactivation of Erk1/2 and Elk-1, and suppressed transcription of early growth response protein 1 and its target genes, basic fibroblast growth factor and platelet-derived growth factor. These data suggest that IGF-independent Erk1/2 inactivation and decreased IGFBP-3–induced Egr-1 expression block the autocrine and paracrine loops of angiogenic factors in vascular endothelial and cancer cells. Together, these findings provide a molecular framework of IGFBP-3's IGF-independent antiangiogenic antitumor activities. Future studies are needed for development of IGFBP-3 as a new line of antiangiogengic cancer drug.


2002 ◽  
Vol 6 (2) ◽  
pp. 190-198 ◽  
Author(s):  
Sergey A Kaliberov ◽  
Donald J Buchsbaum ◽  
G.Yancey Gillespie ◽  
David T Curiel ◽  
Waleed O Arafat ◽  
...  

2015 ◽  
Vol 231 (7) ◽  
pp. 1514-1521 ◽  
Author(s):  
Daniela Frezzetti ◽  
Marianna Gallo ◽  
Cristin Roma ◽  
Amelia D'Alessio ◽  
Monica R. Maiello ◽  
...  

Sign in / Sign up

Export Citation Format

Share Document