Establishment of an in vitro 3D model for neuroblastoma enables preclinical investigation of combined tumor‐stroma drug targeting

Introduction: Transrectal ultrasound (TRUS) prostate biopsy (Bx) is currently confined to 2D information to both target and record 3D Bx locations. Accurate placement of Bx needles cannot be verified without 3D information, and recording Bx sites in 2D does not provide sufficient information to accurately guide the high incidence of repeat Bx. We have designed a 3D TRUS prostate Bx system that augments the current 2D TRUS system and provides tools for biopsy-planning, needle guidance, and recording of the biopsy core locations entirely in 3D. Methods: Our Bx system displays a 3D model of the patient’s prostate, which is generated intra-procedure from a collection of 2D TRUS images, representative of the particular prostate shape. Bx targets are selected, needle guidance is facilitated, and 3D Bx sites are recorded within the 3D context of the prostate model. The complete 3D Bx system was validated, in vitro, by performing standard ten-core Bx on anatomical phantoms of two patient’s prostates. The accuracy of the needle-guidance, Bx location recording, and 3D model volume and surface topology were validated against a CT gold standard. Results: The Bx system successfully reconstructed the 3D patient prostate models with a mean volume error of 3.2 ± 7.6%. Using the 3D system, needles were accurately guided to the pre-determined targets with a mean error of 2.26 ± 1.03 mm and the 3D locations of the Bx cores were accurately recorded with a mean distance error of 1.47 ± 0.79 mm. Conclusion: We have successfully developed a 3D TRUS prostate biopsy system and validated the system in vitro. A pilot study has been initiated to apply the system clinically.

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Phospholipid-Based Prodrugs for Drug Targeting in Inflammatory Bowel Disease: Computational Optimization and In-Vitro Correlation

Current Topics in Medicinal Chemistry ◽

10.2174/1568026616666160414122913 ◽

2016 ◽

Vol 16 (23) ◽

pp. 2543-2548 ◽

Cited By ~ 15

Author(s):

Arik Dahan ◽

Shimon Ben-Shabat ◽

Noa Cohen ◽

Shahar Keinan ◽

Igor Kurnikov ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Drug Targeting ◽

Computational Optimization ◽

Inflammatory Bowel

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The development of an in vitro 3D model of goblet cell hyperplasia using MUC5AC expression and repeated whole aerosol exposures

Toxicology Letters ◽

10.1016/j.toxlet.2021.04.012 ◽

2021 ◽

Author(s):

Linsey E. Haswell ◽

David Smart ◽

Tomasz Jaunky ◽

Andrew Baxter ◽

Simone Santopietro ◽

...

Keyword(s):

Goblet Cell ◽

3D Model ◽

Cell Hyperplasia ◽

Goblet Cell Hyperplasia

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ITGA5 inhibition in pancreatic stellate cells attenuates desmoplasia and potentiates efficacy of chemotherapy in pancreatic cancer

Science Advances ◽

10.1126/sciadv.aax2770 ◽

2019 ◽

Vol 5 (9) ◽

pp. eaax2770 ◽

Cited By ~ 7

Author(s):

Praneeth R. Kuninty ◽

Ruchi Bansal ◽

Susanna W. L. De Geus ◽

Deby F. Mardhian ◽

Jonas Schnittert ◽

...

Keyword(s):

Therapeutic Potential ◽

Tumor Stroma ◽

Stellate Cells ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Tumor Penetration ◽

Desmoplastic Stroma ◽

Integrin Α5

Abundant desmoplastic stroma is the hallmark for pancreatic ductal adenocarcinoma (PDAC), which not only aggravates the tumor growth but also prevents tumor penetration of chemotherapy, leading to treatment failure. There is an unmet clinical need to develop therapeutic solutions to the tumor penetration problem. In this study, we investigated the therapeutic potential of integrin α5 (ITGA5) receptor in the PDAC stroma. ITGA5 was overexpressed in the tumor stroma from PDAC patient samples, and overexpression was inversely correlated with overall survival. In vitro, knockdown of ITGA5 inhibited differentiation of human pancreatic stellate cells (hPSCs) and reduced desmoplasia in vivo. Our novel peptidomimetic AV3 against ITGA5 inhibited hPSC activation and enhanced the antitumor effect of gemcitabine in a 3D heterospheroid model. In vivo, AV3 showed a strong reduction of desmoplasia, leading to decompression of blood vasculature, enhanced tumor perfusion, and thereby the efficacy of gemcitabine in co-injection and patient-derived xenograft tumor models.

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Current trends in mathematical modeling of tumor–microenvironment interactions: a survey of tools and applications

Experimental Biology and Medicine ◽

10.1258/ebm.2009.009230 ◽

2010 ◽

Vol 235 (4) ◽

pp. 411-423 ◽

Cited By ~ 39

Author(s):

Katarzyna A Rejniak ◽

Lisa J McCawley

Keyword(s):

Mathematical Modeling ◽

Protein Interactions ◽

Computational Models ◽

Chemical Species ◽

Tumor Stroma ◽

Cellular Functions ◽

Complex Interactions ◽

Expanding Population

In its simplest description, a tumor is comprised of an expanding population of transformed cells supported by a surrounding microenvironment termed the tumor stroma. The tumor microcroenvironment has a very complex composition, including multiple types of stromal cells, a dense network of various extracellular matrix (ECM) fibers interpenetrated by the interstitial fluid and gradients of several chemical species that either are dissolved in the fluid or are bound to the ECM structure. In order to study experimentally such complex interactions between multiple players, cancer is dissected and considered at different scales of complexity, such as protein interactions, biochemical pathways, cellular functions or whole organism studies. However, the integration of information acquired from these studies into a common description is as difficult as the disease itself. Computational models of cancer can provide cancer researchers with invaluable tools that are capable of integrating the complexity into organizing principles as well as suggesting testable hypotheses. We will focus in this Minireview on mathematical models in which the whole cell is a main modeling unit. We will present a current stage of such cell-focused mathematical modeling incorporating different stromal components and their interactions with growing tumors, and discuss what modeling approaches can be undertaken to complement the in vivo and in vitro experimentation.

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A Minimalistic in Vitro 3D Model to Study F98 Rat Brain Tumor Growth

Biophysical Journal ◽

10.1016/j.bpj.2015.11.1824 ◽

2016 ◽

Vol 110 (3) ◽

pp. 339a

Author(s):

Emilie Gontran ◽

Marjorie Juchaux ◽

Christophe Deroulers ◽

Mathilde Badoual ◽

Olivier Seksek

Keyword(s):

Brain Tumor ◽

Tumor Growth ◽

Rat Brain ◽

3D Model ◽

Rat Brain Tumor

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Tumor-Stroma Crosstalk Enhances REG3A Expressions that Drive the Progression of Hepatocellular Carcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms21020472 ◽

2020 ◽

Vol 21 (2) ◽

pp. 472 ◽

Cited By ~ 2

Author(s):

Yuri Cho ◽

Min Ji Park ◽

Koeun Kim ◽

Jae-Young Park ◽

Jihye Kim ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Microarray Analysis ◽

Cdna Microarray ◽

Tumor Stroma ◽

Mrna Levels ◽

Dependent Manner ◽

Cdna Microarray Analysis ◽

Hcc Cells

Abstract: Background: Crosstalk between tumors and their microenvironment plays a crucial role in the progression of hepatocellular carcinoma (HCC). However, there is little existing information about the key signaling molecule that modulates tumor-stroma crosstalk. Methods: Complementary DNA (cDNA) microarray analysis was performed to identify the key molecule in tumor-stroma crosstalk. Subcutaneous xenograft in vivo murine model, immunoblotting, immunofluorescence, and real-time polymerase chain reaction using HCC cells and tissues were performed. Results: The key molecule, regenerating gene protein-3A (REG3A), was most significantly enhanced when coculturing HCC cells and activated human hepatic stellate cells (HSCs) (+8.2 log) compared with monoculturing HCC cells using cDNA microarray analysis. Downregulation of REG3A using small interfering RNA significantly decreased the proliferation of HSC-cocultured HCC cells in vitro and in vivo, and enhanced deoxycholic acid-induced HCC cell apoptosis. Crosstalk-induced REG3A upregulation was modulated by platelet-derived growth factor ββ (PDGF-ββ) in p42/44-dependent manner. REG3A mRNA levels in human HCC tissues were upregulated 1.8-fold compared with non-tumor tissues and positively correlated with PDGF-ββ levels. Conclusions: REG3A/p42/44 pathway/PDGF-ββ signaling plays a significant role in hepatocarcinogenesis via tumor-stroma crosstalk. Targeting REG3A is a potential novel therapeutic target for the management of HCCs by inhibiting crosstalk between HCC cells and HSCs.

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