Development of Human Tumor Models for Evaluation of Compounds Which Target Tumor Vasculature

There was executed the analysis of thematic literature during from 1956 to 2015 devoted to receptors to fetal proteins, including to alpha-fetoprotein (AFP) known in medicine as oncomarker and used by malignant cells for the organization of tumoral homeostasis. As protein carrier, AFP similar to albumin takes of vitally important molecules in a space «hydrophobic pocket» and moves inside a cell, but as the cancer-embryonal antigen (CEA) - determines the existence of a malignant tumor, but not the type of a neoplasm. On the bounding of AFP with teratogen and their internalization and delivery in an embryo there is based the development of ways of «address» delivery of substances into a cell. This is realized by means of receptor mediated endocytosis via specific membranous receptors to AFP (ReCAF) with high selectivity concerning malignant cells of various genesis. Up to 90% of all malignant cells of the human and tumor models for human and mammalians express AFP receptors, including rather recently opened stem tumor cells - the most probable source of metastasing. AFP production and expression of receptors is selectively raised in malignant tumors of patients and human tumor models. The hyperproduction of AFP and hyperexpression of ReCAF are related to the histologic type of tumor model and are characteristic for embrional cell tumors and hepatoblastomas with initially low drug sensitivity or with the resistance. When choosing the model it is necessary to consider that in different types of tumor cells ReCAF have specific features in cultivation which are not pronounced in conditions of an animal organism. More differentiated tumors are characterized by the larger level of the AFP production and a hyperexpression of ReCAF. The use of subcutaneous tumor xenografts signal for AFP localizations with the hyperexpression of receptors, allows to reveal mostly evidentially the effectiveness of the therapeutic system at the preclinical level. Address delivery of therapeutic systems created on the basis of AFP or its fragments is capable of causing the change of their pharmacological properties. The therapeutic prize is possible due to the induction of process of apoptosis via the mitochondrial pathway, but at the same time the fall in the cytotoxic capacity of system is possible.

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Exercise during preoperative therapy increases tumor vascularity in pancreatic tumor patients

Scientific Reports ◽

10.1038/s41598-019-49582-3 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 9

Author(s):

Claudia Alvarez Florez Bedoya ◽

Ana Carolina Ferreira Cardoso ◽

Nathan Parker ◽

An Ngo-Huang ◽

Maria Q. Petzel ◽

...

Keyword(s):

Vascular Remodeling ◽

Vascular Function ◽

Human Tumor ◽

Tumor Vasculature ◽

Ductal Adenocarcinoma ◽

Tumor Vascularity ◽

Exercise Induced ◽

First Time ◽

Chemotherapy Efficacy ◽

Exercise In Humans

Abstract The efficacy of chemotherapy is reduced by dysfunctional tumor vasculature, which may limit chemotherapy delivery to tumors. Preclinical studies have shown that moderate aerobic exercise improves tumor vascular function and increases chemotherapy efficacy in mouse models, but the effect of exercise on human tumor vasculature has not yet been determined. Here, we demonstrate that exercise remodels the tumor vasculature, accelerates the regression, and delays the regrowth of pancreatic ductal adenocarcinoma in a patient-derived xenograft mouse model treated with gemcitabine. By evaluating pancreatic adenocarcinoma specimens from patients treated with preoperative chemotherapy or chemoradiation therapy, we also demonstrate for the first time that tumor vascular remodeling occurs in association with exercise in humans. Future studies will evaluate whether exercise-induced vascular remodeling improves gemcitabine or other chemotherapy efficacy in patients, as this study evaluated only changes in tumor vascular structure.

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Vascular endothelial growth factor (VEGF) mRNA expression in human tumor models of different histologies

Annals of Oncology ◽

10.1093/oxfordjournals.annonc.a059322 ◽

1995 ◽

Vol 6 (8) ◽

pp. 817-825 ◽

Cited By ~ 55

Author(s):

D.P. Berger ◽

L. Herbstritt ◽

W.A. Dengler ◽

D. Marmé ◽

R. Mertelsmann ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Mrna Expression ◽

Human Tumor ◽

Vascular Endothelial ◽

Tumor Models ◽

Vegf Mrna ◽

Endothelial Growth Factor ◽

Vegf Mrna Expression

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282 POSTER 5-Methyl-indirubin: a CDK-inhibitor with activity in human tumor models in vivo

European Journal of Cancer Supplements ◽

10.1016/s1359-6349(06)70287-7 ◽

2006 ◽

Vol 4 (12) ◽

pp. 89 ◽

Cited By ~ 1

Author(s):

H. Fiebig ◽

A. Maier ◽

J. Schüler ◽

V. Smith ◽

T. Metz

Keyword(s):

Human Tumor ◽

Cdk Inhibitor ◽

Tumor Models

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Pericyte-Coverage of Human Tumor Vasculature and Nanoparticle Permeability

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.35.761 ◽

2012 ◽

Vol 35 (5) ◽

pp. 761-766 ◽

Cited By ~ 29

Author(s):

Liuzhe Zhang ◽

Hiroshi Nishihara ◽

Mitsunobu R Kano

Keyword(s):

Human Tumor ◽

Tumor Vasculature ◽

Pericyte Coverage

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331 MEDI3379, an Antibody Against HER3, is Active in Heregulin or HER2-driven Human Tumor Models

European Journal of Cancer ◽

10.1016/s0959-8049(12)72129-9 ◽

2012 ◽

Vol 48 ◽

pp. 101

Author(s):

P. Steiner ◽

K. Kinneer ◽

K. Schifferli ◽

R. Rothstein ◽

R. Carrasco ◽

...

Keyword(s):

Human Tumor ◽

Tumor Models

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Primary Extracellular Matrix Enables Long-Term Cultivation of Human Tumor Oral Mucosa Models

Frontiers in Bioengineering and Biotechnology ◽

10.3389/fbioe.2020.579896 ◽

2020 ◽

Vol 8 ◽

Author(s):

Leonie Gronbach ◽

Philipp Jurmeister ◽

Monika Schäfer-Korting ◽

Ulrich Keilholz ◽

Ingeborg Tinhofer ◽

...

Keyword(s):

Extracellular Matrix ◽

Oral Mucosa ◽

Hypoxia Inducible Factor ◽

Human Tumor ◽

Patient Specific ◽

Long Term Effects ◽

Tumor Models

3D tumor models clearly outperform 2D cell cultures in recapitulating tissue architecture and drug response. However, their potential in understanding treatment efficacy and resistance development should be better exploited if also long-term effects of treatment could be assessed in vitro. The main disadvantages of the matrices commonly used for in vitro culture are their limited cultivation time and the low comparability with patient-specific matrix properties. Extended cultivation periods are feasible when primary human cells produce the extracellular matrix in situ. Herein, we adapted the hyalograft-3D approach from reconstructed human skin to normal and tumor oral mucosa models and compared the results to bovine collagen-based models. The hyalograft models showed similar morphology and cell proliferation after 7 weeks compared to collagen-based models after 2 weeks of cultivation. Tumor thickness and VEGF expression increased in hyalograft-based tumor models, whereas expression of laminin-332, tenascin C, and hypoxia-inducible factor 1α was lower than in collagen-based models. Taken together, the in situ produced extracellular matrix better confined tumor invasion in the first part of the cultivation period, with continuous tumor proliferation and increasing invasion later on. This proof-of-concept study showed the successful transfer of the hyalograft approach to tumor oral mucosa models and lays the foundation for the assessment of long-term drug treatment effects. Moreover, the use of an animal-derived extracellular matrix is avoided.

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Oligosaccharide Expression and Modification Defines Novel Targets within the Vascular Tree: Selective Chondroitin Sulfate C Expression in the Tumor Microenvironment Generates a Novel Target of Otherwise Constitutive Receptors.

Blood ◽

10.1182/blood.v104.11.2611.2611 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2611-2611

Author(s):

Amr El-Sheikh ◽

Gourab Bhattacharjee ◽

Per Borgstrom ◽

Mattias Belting ◽

Thomas Edgington

Keyword(s):

Tumor Microenvironment ◽

Chondroitin Sulfate ◽

Tumor Vasculature ◽

Heparin Binding ◽

Vascular Tree ◽

Tumor Models ◽

Heparin Binding Domain ◽

Novel Target

Abstract The expression of certain proteoglycans or modification of proteins within the vascular tree, dependent on the microenvironment, is critical for elucidating the biology of endothelium specificity and development. It also facilitates the targeting of physiologic and therapeutic agents to different addresses within the vascular map. Using in vivo panning, we have identified a truncated heparin-binding domain (HBDt) that recognizes its target selectively in tumor vasculature. Here we show that it localizes selectively to the endothelial cells of intra-tumoral blood vessels of various murine tumor models, such as CT26, LLC, N202, and Tramp-L1. The HBDt, as a part of the VEGF heparin-binding domain, is conserved throughout evolution and is known to bind the VEGFR-2/Npn-1 complex. Although the VEGFR-2/Npn-1 complex is expressed elsewhere in the vascular tree, this domain only localizes to a target in tumor vasculature. We have analyzed the basis of this selectivity in vitro and in vivo. In vitro analysis has shown that chondroitin sulfates are the most potent inhibitors of HBDt binding to heparin. We also show, using Western blot and confocal microscopy analyses, that VEGFR-2 and Npn-1, although expressed in different organs, are only recognized by HBDt when coexpressed with chondroitin sulfate C (C6S) in the tumor vasculature. The HBDt colocalized with VEGFR-2, Npn-1, and C6S but with not bFGFR or heparan sulfates in the intravasculature of different tumor models. Furthermore, the selective expression of C6S oligosaccaharide, in conjunction with VEGFR-2 and Npn-1, during the angiogenesis of tumor endothelium defines the target for the HBDt but not during aortic angiogensis. Therefore, our data demonstrate that the expression of C6S, as part of the HBDt receptor, is an example of the tumor microenvironment conditioning, which imparts association of a novel target on endothelium surfaces of tumors.

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