Keywords
Liver - organoids - malignancy
Introduction
Cell is the structures of life, and it is the smallest unit of every living thing.
The life starts from cell. At least, the living thing has to have a cell. The development
of cell is very important for life, and the development of cell is a necessary step
for completeness of life. The defect on development can be expected and this is the
fundamental problem that can further cause the abnormality in life of the living things.
To assess the development problem can provide the answer to many complex medical disorders.
In fact, the basic pathophysiology of any medical disorder can be explained from the
original point at the cellular step. Hence, the cellular study is the important step
for study on pathophysiology in medicine.[1] Although there are many ways to assess the pathophysiology in medical disorder,
the study at cell by means of cellular technology is still a requirement.
At present, there are several new biomedical technologies. Several new advanced cell
technologies are available. Those new technologies can help the medical scientist
to deeply understand the cellular pathological development mechanism. The construction
of cell model to modeling the disorder is the big advent in cellular technology. This
approach can help scientist study of the developmental pathophysiology of the complex
medical disorders.[1] Of several complex medical disorders, cancerous disorder is the important deadly
medical problem group. This problem can be seen worldwide and is still the leading
cause of death of the world population. It can be said that we do largely not know
on the pathophysiology of cancer. Very limited knowledge is available the basic fundamental
developmental pathophysiology of cancer cell.[2] As noted by Dormoy et al., the developmental pathways involved in carcinoma growth identification can be helpful
in understanding the molecular mechanisms of malignancy.[2] In addition, the knowledge can also lead to the improvement of cell based treatment
of the disorders.
Classically, an in vitro experiment on the cancerous tissue is the basic technique
for the study of the pathophysiology of cancer. However, this cannot probe into the
cellular level. The coming of the new molecular technology might be an important part
for understanding of the molecular composition and genetic background of cancer; however,
it does not directly answer the question on cellular abnormality. The cell pathologist
and scientist continuously develop new cell technologies to serve the need for the
advanced techniques to cell pathophysiology clarification. The construction of tissue
model has been done for several years. Several cell cultures are available for cancer
study. Nevertheless, the limitation of the cell culture, lack of reality, is the basic
problem for using cell culture in oncological study. A more complex technique that
can be applied and represent the real situation of the cellular component is healthy
and cancerous situations are still required. How to derive the effective model is
the big question in cell research.[1]
An interesting technology is “organoids”. Organoids is an advanced cell technique
that becomes a new widely used emerging cellular tool for advanced cell research.
In brief, organoids is characterized as a three-dimensional (3D) structure which is
generated by stem cell technique using adult or embryonic stem cells. This structural
model can maintain many structural and functional features of their respective real
organ. As noted by Dahl-Jensen and Grapin-Botton, organoids can answer the problem
of lack of reality of the classical cell culture technique.[3] The organoids can help reflect the developmental step from cell to overt phenotype
in healthy and disorder situation.[3] It can be a useful tool for help medical scientist closely monitor step by step
of development and observe the starting point of the abnormality.[4] A “dynamics of organ development, including the exciting prospect of observing aspects
of human embryo development live”[3] is the core important concept of organoids that becomes the emerging useful tool
for study on cellular pathophysiology.
As already noted, organoids can be used in pathophysiology assessment of several medical
disorders. It can be applied for study of complex genetic disease, serious infection,
and deadly cancer. Due to its use, it can be applied in several branches of medicine.[5]
[6]
[7]
[8]
[9]
[10]
[11] The application in hepatology is also possible and will be further discussed in
this short article. The aim of this review article does not present the original findings
from research but to systematically summarize the available data on this topic. The
overview of state of the art at present is given in [Table 1].
Table 1
Summarization on present status of current organoids research for liver cancer
|
Type of liver cancer
|
Current research
|
|
Primary hepatocellular carcinoma
|
There are many ongoing researches for this type of liver cancer
|
|
Secondary hepatocellular carcinoma
|
Some reports on this type of cancer are available
|
|
Cholangiocarcinoma
|
There is no report on this kind of cancer
|
Organoids for Study of Liver Cancer
Organoids for Study of Liver Cancer
As already mentioned, the use of organoids in the assessment of developmental pathophysiology
is confirmed and applied in several branches of medicine.[12] Starting from potent stem cell, the organoids development using advanced stem cell
technology can help derive a model that can reflect the developmental process of organ
in living things.[12] In hepatology, the development of organoids model is already successful. As noted
by Xu et al., “Together with efficient gene-editing protocol, organoids are emerging as powerful
in vitro disease models.”[13] In fact, the organoids model for liver is a new thing and actual new development
in hepatology.[14]
[15] At present, a small liver cell can be harvested and further used for cell processing
by stem cell technology to provide liver organoids that can be able for further pathophysiology
study.[14]
[15] Mitaka and Ooe noted that the liver organoids is a realistic cellular model since
it can represent the liver tissue’s physiological and biochemical functions.[15] Therefore, the study of several complex hepatic disorders can be based on the organoids
model. This can be applied for several liver diseases including genetic, infectious,
and cancer liver diseases.
In this short article, the author will focus on the cancerous problem. In fact, the
study on liver cancer has been performed in clinical medicine and medical science
for a long time. Within the past few years, there are many interesting new emerging
advanced technologies that help better assess on the liver cancer. Of several new
technologies, the advanced cell technologies for assessment of liver cancer, organoids
technology is very interesting. As noted by Gao and Chen, “cancer ’organoid’ culture
conditions have been developed to establish in vitro growth of patient-derived samples
at higher efficiency and they are very promising for large-scale drug screening and
fundamental cancer biology research.”[16] The author summarizes and discusses on applied organoids technology for studying
on various kinds of liver cancers. The application can be seen on primary hepatocellular
carcinoma, secondary liver cancer, metastatic liver cancer, cholangiocarcinoma, hepatoblastoma,
as well as other rare liver cancers.
Use of Organoids in Pre-Liver Cancer Condition
Use of Organoids in Pre-Liver Cancer Condition
Viral hepatitis
Viral hepatitis is accepted as an important underlying cause of liver cancer. The
hepatitis B virus and hepatitis C virus infections are confirmed as the major causes
of liver cancer worldwide.[17]
[18] The application of organoids technique in viral hepatitis is very interesting. Nevertheless,
according to the literature review, there are extremely few reports on organoids research
for viral hepatitis. A possible reason might be the advanced molecular technology
already helps clarify most problem of pathophysiology of viral hepatitis. Nevertheless,
there is a recent interesting research on using organoids technique to study the antiviral
drug for hepatitis C virus infection in the case of Zika virus infection,[19] which is an actual further application of organoids research on viral hepatitis.
Alcoholic hepatitis
Focusing on alcoholic hepatitis, it is also accepted as an important cause of liver
cancer. Similar to viral hepatitis, there are extremely limited reports on organoids
research for alcoholic hepatitis. According to the record in database (Scopus and
PubMed), there is no report on organoids research on alcoholic hepatitis.
Use of Organoids in Different Kinds of Liver Cancer
Use of Organoids in Different Kinds of Liver Cancer
Primary hepatocellular carcinoma
Organoids research on primary hepatocellular carcinoma is an actual applied organoids
technique in oncology.[20] For hepatocellular carcinoma research, organoids can be used for the assessment
on genetic backgrounds. In addition, the disease modeling can further be useful for
finding a proper personalized cancer therapy planning.[21] The first requirement that brings success for the use of organoids tool in primary
hepatocellular carcinoma research is the success in the development of effective organoids
model. For example, in 2006, there was a report on the successful development of a
new liver organoids based on a functional human hepatocellular carcinoma cell line.[22] The organoids model in that study also made use of mouse cell lines for generation.
This model is the basic reference for further organoids development for primary hepatocellular
research.
Another interesting model was proposed by Kobayashi et al. in 2013.[23] Kobayashi et al. used advanced stem cell technology to manipulate hepatocytes and fibroblasts accompanied
with primary hepatocellular carcinoma cell line to form the organoids model.[23]
In addition to the organoids model development, the actual applied of the developed
model is very interesting. First, the study on genetic underlying of hepatocellular
carcinoma is a good example of application of organoids technique for pathophysiological
study of primary hepatocellular carcinoma. Crosas-Molist et al. studied on the interrelationship between oncogene and hepatoma by mean of organoids
model and concluded the cellular pathophysiological mechanism of tumor aggressiveness
of primary hepatocellular carcinoma.[24] Second, the study on cancer therapy for primary hepatocellular carcinoma by organoids
technique should also be mentioned. In fact, the attempt of using spheroids technique,
which is a preorganoids development, for study in anticancerous agent has been published
for many years.[25] For organoids, Lu et al. recently reported on anticancer effect of triterpenoid preparation using organoids
model.[26] Lu et al. found that triterpenoid preparation had strong cytotoxic effect and also identified
drug–drug interaction according to the studied preparation.[26] This report by Lu et al.[26] is a good example of report from organoids technique that might be further useful
in new anticancer drug search.
Secondary liver cancer
The secondary liver cancer, caused by cancer metastatic cells from other primary origin,
due to other cancer is a common problem in oncology since the liver is the common
site of cancer metastasis. Skardal et al. recently reported an interesting organoids technique research on secondary liver
cancer.[27] Skardal et al. reported the success in developed organoids model of secondary liver cancer due
to colon cancer metastasis and mentioned for using the potential of in vitro 3D liver-tumor
organoids for serving as a model for metastasis growth as well for assessment the
response of malignant cells to present and newly launched drugs.[26]
Metastatic liver cancer
The metastasis of primary hepatocellular carcinoma is a common problem in advanced
primary hepatocellular carcinoma. Metastatic liver cancer, caused by metastatic liver
cancer cells in another organ, is difficult to manage in oncology. Although there
is a success in organoids development for metastatic cancer model, such as model for
metastatic colorectal cancer,[28] there is still no report on the success on the development of organoids model of
metastatic liver cancer.
Cholangiocarcinoma
Cholangiocarcinoma is a common biliary tract cancer. The intrahepatic cholangiocarcinoma
is a deadly liver cancer with a poor prognosis. In tropical Southeast Asia, the relationship
between cholangiocarcinoma and liver fluke infestation is confirmed.[29]
[30] Focusing on the use of organoids model for cholangiocarcinoma research, there is
still no report on success in the development of organoids model for cholangiocarcinoma.
Hepatoblastoma
Hepatoblastoma is an important kind of liver cancer seen in pediatric hepatology.
The application of organoids research on this liver cancer is limited. Nevertheless,
there is an interesting report on using spheroids technique.[31] In that study, Kosaka et al. successfully used spheroid cultures of human hepatoblastoma cells for studying on
alcoholic toxicity and development of cancer.[31] The future organoids development can be referred to the basic information from the
study by Kosaka et al.[31]
Hepatic lymphoma
Hepatic lymphoma is a rare type of liver cancer.[32] Although the development of organoids model for lymphoma is successful,[33] there is still no application on organoids research for hepatic lymphoma.
Conclusion
Organoids is a new cellular technology with used on stem cell knowledge for modeling
realistic model to reflect medical disorder. It can be useful for cellular developmental
pathophysiology study. In hepatology research, the new advanced organoids tool can
be very useful on the etiopathophysiology study of several liver problems including
liver cancer. It is widely applied for studying on several precancer conditions and
several kinds of liver cancer. The rapid progression of the cell biotechnology can
be seen and this is very useful for liver cancer pathophysiology and therapeutic research.
Although the development and maintenance of organoids is still a big technical problem
for many settings, the use of this new cellular tool warrants further attempt of the
medical scientist who works on liver cancer research to learn, develop, and use the
organoids technique for hepatic cancer research and development. The organoids is
an actual hope for the future in hepatology. Nevertheless, it is still far incomplete
in terms of coverage of models. It should be well clarified that there are several
types of organoid culture. Sometimes, the effectiveness of technique is due to the
difference of transport phenomena and diffusion limitation. It is still the interesting
topic for further study on required culture condition for the truly effective organoids.
