April 30, 2019 Critical Thinking

1. Abstract

Liver cancer is a malignant tumor that starts in the cells of the liver and is also the one in the fifth most cancers in the world 1, in most cases liver cancer starts in hepatocytes, the cells which make up the body of the liver. Cancer treatment using stem cells is a fast-growing method to treat many cancers. At present the most common method to treat liver cancer is by surgical approach to remove the affected portion of the liver. But in many cases the cancer spreads very fast and cover most portion of the liver where surgical approaches fail, in this situation treatment by injecting the stem cells becomes significant. In liver cancer, the cancer stem cells (CSCs) is the main reason for the formation, invasion, metastasis, and recurrence of the tumor, this can be identified by using markers, many drugs have been developed to control it. The mechanism of liver cancer treatment, the advantages and disadvantages of this treatment and moreover the recent advancements in the treatment of liver cancer is addressed in this paper. Stem cell treatment improves the outcomes of liver diseases and also helps in development of new drugs.

OPINION PAPER: Stem Cell Therapy in Liver Cancer

2. Introduction

The main objective of this opinion paper is to discuss about liver cancer and the treatment of it using stem cell therapy. Liver cancer or hepatic cancer is one of the most often cancers in the world 1, which is caused due to cirrhosis, aflatoxin, non-alcoholic fatty liver disease and liver flukes, with the symptoms like lump or pain in the right side below the rib cage, yellowish skin, weight loss, swelling of abdomen etc. The most common approaches for the treatment includes surgery, targeted therapy and radiation therapy 4.
Stages of liver cancer


Mechanism of liver cancer

Source: http://tgc.amegroups.com/article/view/90/96

OPINION PAPER: Stem Cell Therapy in Liver Cancer
A normal liver has a very low cell turnover, but when any abnormalities occurs, a rapid regeneration of cells takes place, the actual mechanism is that the injury activates a facultative stem cell compartment present I the intrahepatic biliary tree, which produces cords of biopotential transit amplifying cells which has the capacity to differentiate into hepatocytes and biliary epithelial cells 2. Hepatocytes are the functional stem cells of liver which normally helps in the regeneration of liver. The isolated hepatocytes are first tested in vivo and ex vivo cell therapies but hepatocytes do not survive in in vitro culture and another limitation is the scarcity of donor livers from which hepatocytes are usually isolated leads to the development of the technology called stem cell therapy 6. The capacity of stem cells for differentiation and renewal provides unlimited number of hepatocytes. There are different stem cell sources for the treatment and they are liver- derived stem cells, bone marrow -derived stem cells, annex stem cells, embryonic stem cells(ESCs), induced pluripotent stem cells(iPSCs) 3.
Stem cells in liver disease.


The main benefits of stem cell therapy are that it improves liver function after resection and the advantage of the graft-versus-tumor effect that is mostly seen in allogeneic transplants. In many cases, stem cell therapy can be used prior to surgical removal of the tumors in liver, which improves liver function and avoid complications, stem cells also help in vitro screening
OPINION PAPER: Stem Cell Therapy in Liver Cancer
of new antitumor drugs by providing cellular targets of the tumor’s mutations in cancer patients. Stem cell therapy works by improving the regeneration of liver by modulating liver’s own regeneration process, helps in down- regulate immune mediated liver damage, provides hepatocyte-like cells(HLCs) derived from stem cells and helps to use stem cell derived HLCs for cell transplantation to replace hepatocyte function 6.

Source: http://www.ncrm.org/media/timesofindia20oct11.html

OPINION PAPER: Stem Cell Therapy in Liver Cancer
3. Search strategy

The information gathered in this opinion paper is from different sources. The core source for the paper was web searching or so called online information, that includes articles, review papers, journals. The sites like google scholars, NCBI, PUBMED provided the access to most of the research papers for reference. In some cases, some research papers were not accessible completely, where the abstract was the only source of information. Most of the information in this opinion paper is gathered from online sources. At certain point I was not clear about some terminology and some mechanism of the disease, in that situation all my doubts and clarifications were answered by my friends and seniors, so a verbal way of information gathering also helped me. The images used in the opinion paper was taken from some research papers and with the help of google. The basic knowledge on the mechanism of the disease was provided by the sites like Wikipedia. Gathering data based on clinical trials and the recent advancement in the technology was little tough compared to other information, it was mostly done with the help of recent research paper.

OPINION PAPER: Stem Cell Therapy in Liver Cancer
4. Discussion
Hepatocyte transplantation is a proven alternative approach to liver transplantation, but limited due to availability of organ, failure of donor engraftment and weak viability in cell culture etc. Transplantation of stem cells is effective according to the recent experimental and human studies 11. The stem cells function by improving the microenvironment through paracrine effects, and the replacement of functional hepatocytes 11. The stem cells derived from adult livers are bipotent and can differentiate into hepatocytes or bile duct cells, these cells play a vital role in liver regeneration. The main limitation is that their number within a normal liver is very low, thus isolation is not practical. The hematopoietic and mesenchymal stem cells from bone marrow are multipotent progenitor cells which are easily accessible and isolated. They also have immunomodulatory or immunosuppressive properties that down regulate T cell, B cell, and NK cell functions, thus they induce tolerance after liver transplantation. ESCs are totipotent cells which can colonize the liver after injury 3. But the limitation of this is that their procurement involves the destruction of embryos and there will be immune incompatibility between donors and recipients. iPSCs are like ESCs, and they offer possibility for autologous use. The origin of the iPSCs play an important role in their capacity to differentiate. Adoptive immunotherapy, with the transfer of naturally occurring T cells is an effective method for cancer treatment, this same technique can be performed using iPSCs, which is able to supply highly reactive antigen specific cytotoxic T- lymphocytes that can target, infiltrate and eradicate tumors when transferred into patients 7. Using all these different stem cells the liver cancer can be treated, thus stem cell therapy is an emerging field for cancer treatment. The clinical studies documented that there where improvements in liver function and enhanced liver regeneration after portal vein embolization, it is a radiological approach to block the venous flow to affected part of the liver and after surgical removal of the affected area of the liver. The most common treatments available for liver cancer is surgery (liver resection and liver transplant), Trans arterial chemoembolization (TACE), ablation therapies (Radiofrequency ablation (RFA) and Percutaneous ethanol injection (PEI), targeted therapy and radiation therapy 12.
OPINION PAPER: Stem Cell Therapy in Liver Cancer
5. Future Directions

Progenitor cell lines derived from normal human liver will be a source of hepatocytes, there are further improvement going on the isolation, cultivation and propagation techniques. The studies done in rodents shows that human fetal liver progenitor cells have proliferated, and this could be done in humans in future. More researches are needed to identify the inside and outside of the liver which can form hepatocytes in vitro and functional liver tissue after transplantation in vivo 48. The preliminary results of the clinical trials are positive, but the safety and efficacy of the adult stem cell therapy is a major concern. Regenerating medicine involving the stem cells is rapidly growing and many researches is done in this field and clinical trials are carried out. In future the exploration of this method for the treatment of liver cancer will happens, which benefits the patients suffering from liver diseases mostly who are in the end stages. Before using this therapy in clinical applications, different aspects must be taken into consideration which include, efficient differentiation into mature hepatocytes should be done without the help of viral vectors to avoid tumorigenicity 6. An efficient and reliable method for rapid and large-scale production of cells need to be developed. Significant progress has seen in liver stem cell studies in the last few years 9. The need to study the normal liver cells and the cancerous liver stem cells are clear and studies are going on. Tumor initiating stem- like cells(TISC) that occur during liver injury share expression of signaling pathways, which include those organised around TGF-And ?- catenin, surface markers with normal LPC. Researches on role of TISC in hepatocellular carcinoma provides details about the transcriptional and posttranscriptional regulation of hepatocarcinogenetic 10. The focus is on new markers of normal LPCs which may be useful for further fractionation of heterogeneous TISC populations. And in the same hand the role of signaling pathways and transcription factors regulating TISC characteristics in noncancerous liver regeneration is studied in detail. Overall, treatment of liver cancer with the help of stem cells will be a promising strategy, and more advancements will happen in this field.