Okayama University Research: 3D Tissue Model Offers Insights Into Treating Pancreatic Cancer

OKAYAMA, Japan, January 31, 2019 /PRNewswire/ --

Researchers at Okayama University show how specific cells of the pancreas can facilitate cancer progression

Pancreatic cancer can be fatal. It is extremely difficult to treat partly because its precise growth mechanism is not clear. One of the characteristics of pancreatic cancer is the presence of fibrous structures or 'desmoplasia' that are found in conjunction with the tumour. Scientists at Okayama University have recently clarified the structure and the mechanisms underlying the emergence of desmoplasia in pancreatic cancer.

(Photo: https://mma.prnewswire.com/media/816116/PSC_Tissue_Samples.jpg )

To understand desmoplasia better it must be replicated in the laboratory. Here, the researchers first analysed desmoplasia from human samples of pancreatic cancer. Microscopy revealed that cancer cells were separated from surrounding blood vessels by fibrous desmoplasia cells. The desmoplasia layer was about 10 to 30 micrometers thick, suggesting that if a therapeutic agent were to reach cancer cells from the blood it would have to traverse this distance-a key factor determining the efficiency of drug delivery.

Next, the researchers extracted pancreatic stellate cells (PSCs) from patients to create a 3D model of desmoplasia because desmoplasia is formed of these cells. Arranging PSCs in increasing numbers quickly resulted in layers at least 10 micrometers thick, accurately mimicking the desmoplasia in pancreatic cancer. The normal function of PSCs is to secrete the extracellular matrix (ECM), which is a support system that holds cells together. The composition and organization of ECM is severely altered in the desmoplasia. This led the researchers to use their 3D model to understand how ECM changes occur and the role of PSCs with respect to these changes.

The model showed the abundance of two ECM components, Fibronectin and Collagen, just as seen in patient desmoplasia. Notably, these components also act as barriers preventing drugs from reaching cancer cells. The trigger that drives the switch between normal ECM and the aberrant ECM in desmoplasia was a major pathway mediated by a pair of proteins TGF-ß/ROCK. Activation of this pathway could not only switch healthy fibrous cells into the toxic PSCs, but also result in increases of Collagen and Fibronectin. Lastly, another cancer protein, SPARC, was also found to be involved with these ECM abnormalities, further establishing its relevance to pancreatic cancer.

This was the first study to replicate a 3D model of desmoplasia in the laboratory, with relevance to clinical samples. This model successfully revealed toxic pathways that are activated in pancreatic cancer. Such a model has wide ranging implications such as deeper insights into structural and molecular aberrations that drive the disease with the possibility of discovering how to overcome the desmoplastic barrier to facilitate drug delivery to tumour cells.

This work has been carried out by a collaborative research with scientists in Tohoku University, Keio University, Osaka University, Hirosaki University, Japan Women's University, and Toyo University.

Background

Extracellular matrix (ECM): The ECM is a scaffold made up of different biochemical components. This scaffolding network that is secreted by specific kinds of cells, functions to hold and bind cells in place and facilitate communication between them. It thus acts as an external system keeping cells healthy, strong and functioning correctly. Alterations in the ECM can lead to cellular dysfunction, such as in cancer.

Reference

Hiroyoshi Y. Tanaka, Kentaro Kitahara, Naoki Sasaki, Natsumi Nakao, Kae Sato, Hirokazu Narita, Hiroshi Shimoda, Michiya Matsusaki, Hiroshi Nishihara, Atsushi Masamune, Mitsunobu R. Kano. Pancreatic stellate cells derived from human pancreatic cancer demonstrate aberrant SPARC-dependent ECM remodeling in 3D engineered fibrotic tissue of clinically relevant thickness. Biomaterials, 2019 Feb;192:355-367.

DOI: 10.1016/j.biomaterials.2018.11.023.

https://www.sciencedirect.com/science/article/pii/S0142961218308007?via%3Dihub

Okayama University Medical Research Updates(OU-MRU)

The whole volume: OU-MRU (1- )

Vol.1:Innovative non-invasive 'liquid biopsy' method to capture circulating tumor cells from blood samples for genetic testing

Vol.2:Ensuring a cool recovery from cardiac arrest

Vol.3:Organ regeneration research leaps forward

Vol.4:Cardiac mechanosensitive integrator

Vol.5:Cell injections get to the heart of congenital defects

Vol.6:Fourth key molecule identified in bone development

Vol.7:Anticancer virus solution provides an alternative to surgery

Vol.8:Light-responsive dye stimulates sight in genetically blind patients

Vol.9:Diabetes drug helps towards immunity against cancer

Vol.10:Enzyme-inhibitors treat drug-resistant epilepsy

Vol.11:Compound-protein combination shows promise for arthritis treatment

Vol.12:Molecular features of the circadian clock system in fruit flies

Vol.13:Peptide directs artificial tissue growth

Vol.14:Simplified boron compound may treat brain tumours

Vol.15:Metamaterial absorbers for infrared inspection technologies

Vol.16:Epigenetics research traces how crickets restore lost limbs

Vol.17:Cell research shows pathway for suppressing hepatitis B virus

Vol.18:Therapeutic protein targets liver disease

Vol.19:Study links signalling protein to osteoarthritis

Vol.20:Lack of enzyme promotes fatty liver disease in thin patients

Vol.21:Combined gene transduction and light therapy targets gastric cancer

Vol.22:Medical supportive device for hemodialysis catheter puncture

Vol.23:Development of low cost oral inactivated vaccines for dysentery

Vol.24:Sticky molecules to tackle obesity and diabetes

Vol.25:Self-administered aroma foot massage may reduce symptoms of anxiety

Vol.26:Protein for preventing heart failure

Vol.27:Keeping cells in shape to fight sepsis

Vol.28:Viral-based therapy for bone cancer

Vol.29:Photoreactive compound allows protein synthesis control with light

Vol.30:Cancer stem cells' role in tumor growth revealed

Vol.31:Prevention of RNA virus replication

Vol.32:Enzyme target for slowing bladder cancer invasion

Vol.33:Attacking tumors from the inside

Vol.34:Novel mouse model for studying pancreatic cancer

Vol.35:Potential cause of Lafora disease revealed

Vol.36:Overloading of protein localization triggers cellular defects

Vol.37:Protein dosage compensation mechanism unravelled

Vol.38:Bioengineered tooth restoration in a large mammal

Vol.39:Successful test of retinal prosthesis implanted in rats

Vol.40:Antibodies prolong seizure latency in epileptic mice

Vol.41:Inorganic biomaterials for soft-tissue adhesion

Vol.42:Potential drug for treating chronic pain with few side effects

Vol.43:Potential origin of cancer-associated cells revealed

Vol.44:Protection from plant extracts

Vol.45:Link between biological-clock disturbance and brain dysfunction uncovered

Vol.46:New method for suppressing lung cancer oncogene

Vol.47:Candidate genes for eye misalignment identified

Vol.48:Nanotechnology-based approach to cancer virotherapy

Vol.49:Cell membrane as material for bone formation

Vol.50:Iron removal as a potential cancer therapy

Vol.51:Potential of 3D nanoenvironments for experimental cancer

Vol.52:A protein found on the surface of cells plays an integral role in tumor growth and sustenance

Vol.53:Successful implantation and testing of retinal prosthesis in monkey eyes with retinal degeneration

Vol.54:Measuring ion concentration in solutions for clinical and environmental research

Vol.55:Diabetic kidney disease: new biomarkers improve the prediction of the renal prognosis

Vol.56:New device for assisting accurate hemodialysis catheter placement

Vol.57:Possible link between excess chewing muscle activity and dental disease

Vol.58:Insights into mechanisms governing the resistance to the anti-cancer medication cetuximab

Vol.59:Role of commensal flora in periodontal immune response investigated

Vol.60:Role of commensal microbiota in bone remodeling

Vol.61:Mechanical stress affects normal bone development

About Okayama University

Okayama University is one of the largest comprehensive universities in Japan with

roots going back to the Medical Training Place sponsored by the Lord of Okayama and

established in 1870. Now with 1,300 faculty and 13,000 students, the University offers

courses in specialties ranging from medicine and pharmacy to humanities and physical

sciences. Okayama University is located in the heart of Japan approximately 3 hours west of

Tokyo by Shinkansen.

Website: http://www.okayama-u.ac.jp/index_e.html

Correspondence to
Professor Mitsunobu Kano, M.D., Ph.D.
Department of Pharmaceutical Biomedicine,
Okayama University Graduate School of Interdisciplinary Science and
Engineering in Health Systems, 1-1-1 Tsushima-naka, Kita-Ku,
Okayama, 700-8530, Japan.
E-mail: [e-mail]

Further information
Okayama University
1-1-1 Tsushima-naka , Kita-ku , Okayama 700-8530, Japan
Public Relations and Information Strategy
E-mail: [e-mail]

Website: http://www.okayama-u.ac.jp/index_e.html
Okayama Univ. e-Bulletin: http://www.okayama-u.ac.jp/user/kouhou/ebulletin/
About Okayama University (YouTube):
https://www.youtube.com/watch?v=iDL1coqPRYI
Okayama University Image Movie (YouTube):
https://www.youtube.com/watch?v=KU3hOIXS5kk