Tumor activation alters the mechano-responsiveness, capillary formation, and drug sensitivity of endothelial cells in synthetic matrices. The study uses synthetic hydrogel cell culture platforms to show that activation of human umbilical endothelial cells (HUVECs) by tumor factors changes the cells' responses to matrix stiffness. Without activation, HUVECs prefer a substrate of appropriate stiffness for optimal capillary formation. However, tumor activation disrupts this mechano-responsive behavior and capillary formation depends less on matrix stiffness. The response of HUVECs to an anti-angiogenic drug was also substrate dependent, with increased drug sensitivity on more compliant gels.
Development of cancer therapeutics is often carried out in 2D cultures prior to testing on animal model. In comparison to 2D cultures, discuss the potential of using 3D in vitro models for drug efficiency testing.
3D culture in phenotypic screening : advantages, process changes and new tech...HCS Pharma
It was a real pleasure to be in the « High-Content and Phenotypic Screening » meeting in Cambridge. We were invited by our partner Molecular Devices to give a talk during the "User meeting Molecular Devices" about our vision of 3D culture in phenotypic screening and the impact of new technologies. We also presented a poster about "Neurotoxicity assay on 2D and 3D culture using High Content Screening technology".
Development of cancer therapeutics is often carried out in 2D cultures prior to testing on animal model. In comparison to 2D cultures, discuss the potential of using 3D in vitro models for drug efficiency testing.
3D culture in phenotypic screening : advantages, process changes and new tech...HCS Pharma
It was a real pleasure to be in the « High-Content and Phenotypic Screening » meeting in Cambridge. We were invited by our partner Molecular Devices to give a talk during the "User meeting Molecular Devices" about our vision of 3D culture in phenotypic screening and the impact of new technologies. We also presented a poster about "Neurotoxicity assay on 2D and 3D culture using High Content Screening technology".
A normal cell can be transformed into a cancerous cell. Discuss the therapeutic strategies that are employed to target the cellular transformation process for cancer prevention and treatment.
Stem cells have the ability to perpetuate themselves through self-renewal and generate mature cells of a particular tissue through differentiation. Mesenchymal Stem Cells (MSCs) play an important role in tissue homeostasis supporting tissue regeneration. MSCs are rare pluripotent cells supporting hematopoietic and mesenchymal cell lineages. MSCs have a great potential in cancer therapy, also the stem cell exosome and/or microvesicle-mediated tissue regeneration abilities may be used a potential to the therapeutic applications. In this review, use of hMSCs in stem cell-mediated cancer therapy is discussed.
Proteogenomic analysis of human colon cancer reveals new therapeutic opportun...Gul Muneer
We performed the first proteogenomic study on a prospectively collected colon cancer cohort. Comparative proteomic and phosphoproteomic analysis of paired tumor and normal adjacent tissues produced a catalog of colon cancer-associated proteins and phosphosites, including known and putative new biomarkers, drug targets, and cancer/testis antigens. Proteogenomic integration not only prioritized genomically inferred targets, such as copy-number drivers and mutation-derived neoantigens, but also yielded novel findings. Phosphoproteomics data associated Rb phosphorylation with increased proliferation and decreased apoptosis in colon cancer, which explains why this classical tumor suppressor is amplified in colon tumors and suggests a rationale for targeting Rb phosphorylation in colon cancer. Proteomics identified an association between decreased CD8 T cell infiltration and increased glycolysis in microsatellite instability-high (MSI-H) tumors, suggesting glycolysis as a potential target to overcome the resistance of MSI-H tumors to immune checkpoint blockade. Proteogenomics presents new avenues for biological discoveries and therapeutic development.
Genes and Tissue Culture Technology Assignment (G6)Rohini Krishnan
The culture of cells in two dimensions does not reproduce the histological characteristics of a tissue for informative or useful study. Growing cells as three-dimensional (3D) models more analogous to their existence in vivo may be more clinically relevant.
Aligned nanofibrillar collagen scaffolds – Guiding lymphangiogenesis for trea...Mary Fickling
Secondary lymphedema is a common disorder associated with acquired functional impairment of
the lymphatic system. The goal of this study was to evaluate the therapeutic efficacy of aligned nanofibrillar collagen scaffolds (BioBridge) positioned across the area of lymphatic obstruction in
guiding lymphatic regeneration.
A normal cell can be transformed into a cancerous cell. Discuss the therapeutic strategies that are employed to target the cellular transformation process for cancer prevention and treatment.
Stem cells have the ability to perpetuate themselves through self-renewal and generate mature cells of a particular tissue through differentiation. Mesenchymal Stem Cells (MSCs) play an important role in tissue homeostasis supporting tissue regeneration. MSCs are rare pluripotent cells supporting hematopoietic and mesenchymal cell lineages. MSCs have a great potential in cancer therapy, also the stem cell exosome and/or microvesicle-mediated tissue regeneration abilities may be used a potential to the therapeutic applications. In this review, use of hMSCs in stem cell-mediated cancer therapy is discussed.
Proteogenomic analysis of human colon cancer reveals new therapeutic opportun...Gul Muneer
We performed the first proteogenomic study on a prospectively collected colon cancer cohort. Comparative proteomic and phosphoproteomic analysis of paired tumor and normal adjacent tissues produced a catalog of colon cancer-associated proteins and phosphosites, including known and putative new biomarkers, drug targets, and cancer/testis antigens. Proteogenomic integration not only prioritized genomically inferred targets, such as copy-number drivers and mutation-derived neoantigens, but also yielded novel findings. Phosphoproteomics data associated Rb phosphorylation with increased proliferation and decreased apoptosis in colon cancer, which explains why this classical tumor suppressor is amplified in colon tumors and suggests a rationale for targeting Rb phosphorylation in colon cancer. Proteomics identified an association between decreased CD8 T cell infiltration and increased glycolysis in microsatellite instability-high (MSI-H) tumors, suggesting glycolysis as a potential target to overcome the resistance of MSI-H tumors to immune checkpoint blockade. Proteogenomics presents new avenues for biological discoveries and therapeutic development.
Genes and Tissue Culture Technology Assignment (G6)Rohini Krishnan
The culture of cells in two dimensions does not reproduce the histological characteristics of a tissue for informative or useful study. Growing cells as three-dimensional (3D) models more analogous to their existence in vivo may be more clinically relevant.
Aligned nanofibrillar collagen scaffolds – Guiding lymphangiogenesis for trea...Mary Fickling
Secondary lymphedema is a common disorder associated with acquired functional impairment of
the lymphatic system. The goal of this study was to evaluate the therapeutic efficacy of aligned nanofibrillar collagen scaffolds (BioBridge) positioned across the area of lymphatic obstruction in
guiding lymphatic regeneration.
2D CAT Based Modeling of Tumour Growth and Drug TransportEditor IJMTER
The transition of normal cells in the tissue that leads into tumour and spreads throughout
depending upon its behavioural conditions is a complex biological process studied through the use of
both in vivo and in vitro experimentation. Mathematical models provide the approach by using a
controlled environment in which a system can be described quantitatively. This can also yield data
which predicts the behaviour of cells and likely medical conditions after thorough analysis by the
modeller. In an effort to study the characteristics that increase cell fitness, the paper presents a 2D
Cellular Automaton model that uses computer simulation to describe the invasion of healthy tissue
by cancer cells. The growth process is simulated and it was found that movement of cells affects
tumour growth rate. It was also found that the relative distance of the tumour initiation area from
neighbouring vessels influences the growth of tumour. The model and the simulation software
developed thus can be used to understand the dynamics of early tumour growth and to explore
various hypotheses of tumour growth relevant to drug delivery in chemotherapy. Importantly, this
approach highlights that vessel displacement should not be neglected in tumour growth models. The
paper thus presents two models i.e cancer growth model and drug transport model for tumour growth
and treatment that will help to diagnose the early tumour growth. Though cancer is uncurable;early
and quick detection of cancer will help doctors in better way by suggesting quick remedial action
against it.
CHI's Targeting Stromal Cells in Cancer and Inflammatory Diseases Conference ...James Prudhomme
This virtual meeting will highlight cutting-edge science and provide insight into recent developments towards therapeutic stromal cell targeting in cancer and chronic inflammatory diseases. View full details and register: https://www.healthtech.com/stroma-conference
Stem cells and nanotechnology in regenerative medicine and tissue engineeringDr. Sitansu Sekhar Nanda
Alexis Carrel, winner of the Nobel Prize in Physiology or Medicine in 1912 and the father of whole-organ transplant, was the first to develop a successful technique for end to end arteriovenous anastomosis in transplantation.
Tumor angiogenesis is currently one of the key focal points in biomedical research. It is based upon the hypothesis laid out by Judah Folkman in 1971 that neovasculature is needed to support the growth and metastasis of tumors, and thus anti-angiogenic treatment might be an effective way to cure cancer. Genentech’s anti-VEGF-A drug Avastin a great demonstration of this concept, generating more than $2.7 billion of sales in 2008.
A physical sciences network characterization of non-tumorigenic and metastati...Shashaanka Ashili
To investigate the transition from non-cancerous to metastatic from a physical sciences perspective, the
Physical Sciences–Oncology Centers (PS-OC) Network performed molecular and biophysical comparative studies of the non-tumorigenic MCF-10A and metastatic DA-MB-231 breast epithelial cell lines, commonly used as models of cancer metastasis. Experiments were performed in 20 laboratories from 12 PS-OCs. Each laboratory was supplied with identical aliquots and common reagents and culture protocols. Analyses of these measurements revealed dramatic differences in their mechanics, migration, adhesion, oxygen response, and proteomic profiles. Model-based multi-omics approaches identified key differences between these cells’ regulatory networks involved in morphology and survival. These results provide a multifaceted description of cellular parameters of two widely used cell lines and demonstrate the value of the PS-OC Network approach for integration of diverse experimental observations to elucidate the phenotypes associated with cancer metastasis.
Synergy of Material, Structure and Cell -Crimson Publishers
Yang poster-BMES 2014
1. Tumor activation alters the mechano-responsiveness, capillary formation, and drug sensitivity of endothelial
cells in synthetic matrices
Yang Wu, Bingxin Guo, and Gargi Ghosh
Bioengineering Program, Department of Mechanical Engineering
University of Michigan - Dearborn
Introduction
Solid cancers induce the formation of new blood vessels to promote
growth and metastasis. Past efforts have been focused on
characterizing the altered growth factor signaling pathway in tumor
capillary endothelial cells; however, the mechanical microenvironment
of tumor also plays a significant role in regulating the formation of
vascular patterns.
Here, we used synthetic hydrogel based cell culture platforms to probe
how activation of human umbilical endothelial cells (HUVECs) by tumor
secreted factors alters the responses to matrix modulus and in turn the
capillary network formation and drug sensitivity.
2).Poro size
3). Diffusion
4) . Morphology images in HR and HCR media
5) . Sprout images on with and W/O cancer cells scaffolds
Goals
Understand how tumor activation affect mechanosensitivity of
endothelial cells
Understand how matrix stiffness and tumor activation affect
response of endothelial cells to vandetanib inhibition
Materials and Methods
Cancer cells
Pre-polymer solution
Cancer cell laden scaffolds
UV curing
Addition of
HUVECs on
the top of cell
laden scaffolds
Capillary sprouts
+
Results
11 kPa 78 kPa36 kPa
0
200
400
600
800
1000
1200
0 10 20 30
Cummulativerelease
ofFITC-dextran(ng)
Time (hour)
11 kPa
36 kPa
78 kPa
Conclusion/ Future Studies
Acknowledgement
Authors would like to thank University of Michigan, Dearborn and
Office of Vice President of Research, University of Michigan, Ann
Arbor for their financial support
Our study revealed that while in absence of activation, HUVECs
prefer a substrate of appropriate stiffness for optimal capillary
network formation; tumor activation disrupts the mechano-
responsive behavior of HUVECs.
on reducing the capillary network was also investigated. The
response of HUVECs to the anti-angiogenic agent was substrate
modulus dependent displaying increased sensitivity on the
compliant gels.
6). Vandetanib inhibition on with and W/O cancer cells
scaffolds
7). IC50 of Vandetanib (µM)
1. Scaffold characterization
1). Compression modulus and swelling ratio
0
5
10
15
20
25
11 36 78
SwellingRatio
Compression Modulus (kPa)
0
10
20
30
40
50
60
70
80
90
5% 10% 15%
Compression
modulus(KPa)
Concentration of PEGDA
Compression
Modulus (kPa)
Without cancer
cells
With cancer cells
11 0.14 0.24
36 0.16 0.36
78 0.21 0.57
11 KPa 36 KPa 78 KPa
36 KPa11 KPa 78 KPa
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
**
*
*
*
*
*
*
11 KPa 36 KPa 78 KPa
36 KPa11 KPa 78 KPa
HR media
HCR media
With
cancer
cells
Without
cancer
cells
0
1
2
3
4
5
0 0.5 1 2
Sproutspernodes
(withcancercells)
Drug concentration ( µM)
11 kPa
36 kPa
78 kPa
0
0.5
1
1.5
2
2.5
3
3.5
4
0 0.5 1 2
Sproutspernodes
(withoutcancercells)
Drug concentrtion (µM)
11 kPa
36 kPa
78 kPa