Source: Okayama University (JAPAN), Public Relations Division
For immediate release: 28 August 2020
Okayama University research: A novel 3D cell culture model sheds light on the mechanisms driving fibrosis in pancreatic cancer
(Okayama, 28 August) In a recent study published in Biomaterials,
researchers at Okayama University created a new 3D cell culture model of
pancreatic cancer that closely mimics the “fibrotic” tissue
characteristically observed in patients.
Pancreatic cancer is a lethal condition with a very poor prognosis—only
~9% of patients live to see another 5 years after diagnosis. A prime
feature of pancreatic cancer is the presence of fibrotic tissue within
the tumors. This fibrotic tissue is akin to the scarring that surrounds a
wound. Fibrotic tissue entraps the cancer cells within it, making it
difficult to therapeutically target these cells. Thus, understanding the
mechanisms behind fibrotic tissue development is imperative for
creating effective treatment strategies. Professor Mitsunobu R. Kano and
Assistant Professor Hiroyoshi Y. Tanaka from Okayama University and
colleagues have now created a three-dimensional (3D) cell culture model
of pancreatic cancer in the laboratory which closely replicate the
fibrotic nature of the tumors.
Fibrotic tissue develops when cancer cells and specialized cells called
fibroblasts closely interact with each other. The patterns of fibrotic
tissue seen in pancreatic cancer vary greatly from patient to patient.
The researchers started by analyzing patient tumor samples and found
that fibrotic tissue took up as little as 40% and as much as 80% of the
space within tumors. For the 3D cell culture model to truly mimic the
cancer, it would need to reflect this wide range in the amount of
fibrotic tissue observed. To achieve this, the team tried seeding
pancreatic cancer cells and fibroblasts at different ratios. Indeed, by
trying various ratios, the team could create 3D pancreatic cancer
tissues with any given amount of fibrotic tissue—most importantly within
the clinically observed range.
The fibroblasts within these models were subsequently scrutinized to
unravel cellular changes driving fibrotic tissue development. It was
found that two proteins, namely, SMAD2/3 and YAP were the driving force
behind such changes. These two proteins, however, did not act alone: the
combined activity of SMAD2/3 and YAP were necessary for the fibroblasts
to acquire the abnormal characteristics seen in tumor tissue. A host of
cellular signaling systems were in place to enable the function of
SMAD2/3 and YAP—some of these systems were common while others were
unique to each protein.
Cell culture models of pancreatic cancer play an indispensable part in
understanding the disease since they allow mechanistic analyses at a
detail that would otherwise be difficult to achieve in studies using
laboratory animals or clinical specimens. However, cell culture models
to date generally failed to recreate the characteristic, densely
fibrotic tissue observed in pancreatic cancer, much less the variability
observed between patients. The 3D cell culture model of pancreatic
cancer developed in this study overcomes these issues. The new model may
enable researchers to understand the differences between tumors showing
various degrees of fibrosis and potentially customize strategies to
target them. “Our novel model will be useful in promoting the
understanding of the complex mechanisms by which the fibrotic stroma
develops and how it might be therapeutically targeted”, conclude the
researchers.
Background
Pancreatic cancer and fibrotic tissue: Pancreatic cancer is one of the
most difficult to treat cancers. This is in large part due to the dense,
fibrotic tissue present within the tumor.
Fibrosis is a biological process that occurs in damaged internal organs
(such as the pancreas) when wound healing mechanisms go awry. Although
fibrosis initiates as a process that protects a damaged organ, it
sometimes also ends up creating an environment that promotes the growth
of cancer cells. Thus, fibrotic tissue is closely associated with the
presence and spread of pancreatic cancer. Fibrotic tissue also
facilitates drug resistance thereby preventing the cancer cells from
responding to any medication. Fibrotic tissue is therefore a huge
barrier to understanding the complexities of pancreatic cancer and
developing therapeutic strategies.
Reference
Hiroyoshi Y. Tanaka, Tsuyoshi Kurihara, Takuya Nakazawa, Michiya
Matsusaki, Atsushi Masamune, Mitsunobu R. Kano. Heterotypic 3D
pancreatic cancer model with tunable proportion of fibrotic elements.
Biomaterials, Volume 251, August 2020, 120077.
DOI : 10.1016/j.biomaterials.2020.120077
Reference (Okayama Univ. e-Bulletin): Professor KANO’s team
OU-MRU Vol.62：https://www.okayama-u.ac.jp/eng/research_highlights/index_id79.html
Correspondence to
Professor KANO Mitsunobu, 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: mitkano(a) okayama-u.ac.jp
For inquiries, please contact us by replacing (a) with the @ mark.
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