Pediatric Hepatoblastoma: Outlining the Causes and Treatment

Abstract

Cancer is a complicated disease affecting many people today. It is the second deadliest disease in America. Pediatric Hepatoblastoma is rare liver cancer among children. Usually affecting children under the age of three, it is very difficult to treat due to its aggressiveness and often has a poor prognosis. Common methods of treatment include tumor resection, chemotherapy, and liver transplant. Researchers are currently involved in many ongoing experiments to learn more about the origination of this disease and new pathways of successful treatment. Novel treatments are a major area of research currently underway. Finally, the biblical perspective of cancer is looked at as to whether God causes cancer and how Christians should react when they or someone they know is diagnosed with cancer.

General Overview

Cancer is a group of diseases characterized by abnormal cells which divide uncontrollably at a rapid rate instead of going through apoptosis (programmed cell death) (Cancer, 2015). Once a tumor forms, it may spread, or metastasize, and invade other parts of the body via the blood stream or lymphatic system and from secondary tumors. Cancer cells constantly mutate and evolve which is part of the reason cancer is such a difficult disease to treat (Alberts, 2014, p.715). Environment, lifestyle, diet, genetics, and physical activity can all play a role in cancer development (What is Cancer, n.d.). According to Alberts (2014), where people live is actually a bigger risk factor than where they were born (p.713).

Regardless of the cause, according to the Center for Disease Control and Prevention (CDC), in 2013, cancer was the second highest cause of death in America (Leading Causes, 2015). In 2014, cancer claimed the lives of 585,720 Americans (Cancer Facts & Figures 2014, n.d.). For 2015, it is estimated that 1,250 children under the age of fifteen will die from cancer, while 10,380 children alone will be diagnosed with cancer (What are the key statistics for childhood cancer? n.d.). One percent of those 10,380 children will be diagnosed with hepatoblastoma, (Reikes-Willert, 2014).

Pediatric Hepatoblastoma (HB) is the most commonly diagnosed liver cancer in children, most often during the first three years of life (Reikes-Willert, 2014). Most HB tumors originate in the right lobe of the liver and will frequently metastasize to the lungs (About Hepatoblastoma, n.d.). Doctors around the world are researching the exact cause of pediatric hepatoblastoma as it is largely unknown. However, a correlation has been found between HB and conditions such as Beckwith-Weidman syndrome, an overgrowth disorder, and familial adenomatous polyposis, which causes abnormal growths in places such as the large intestine. Prematurity or low birthweight have also been found to be associated with the development of this disease (Aronson, 2014).

Further research into the mutations that cause Beckwith-Weidman syndrome and familial adenomatous polyposis are currently underway to help physicians better understand the formation and development of HB. Angiogenesis (the formation of blood vessels) inhibitors are also of special interest as they may be able to prevent the growth of tumors by blocking the formation of new blood vessels that feed the tumors. Some research is also being done to try and use the body’s own immune system to fight off the cancer cells (Childhood Hepatoblastoma, n.d.).

Cell and Molecular Biology

The cell cycle of humans consists of four phases: G1 (growing) phase, S phase (DNA replication,) G2 Phase, and M phase. Within the M phase, there are two more steps called mitosis (nuclear division) and cytokinesis (cell division.) The cell-cycle has a system of checks and balances. This system depends on cyclin-dependent protein kinases (Cdks,) which are cyclically activated by the binding of cyclin proteins and phosphorylation or dephosphorylation (the binding or removal of phosphate groups respectively.) When Cdks are activated, they phosphorylate key proteins within the cell to carry out the correct process of cell reproduction. Sometimes, a mistake occurs somewhere along the way in the cell cycle (Alberts, 2014). Usually when this happens, proteins, such as tumor suppressor protein p53, promote the release of a protein called cytochrome c from the mitochondria, which activates enzymes called caspases (Schuler, 2000). These enzymes carry out apoptosis by deconstructing the cell. Sometimes, mutations in the genetic material, such as deletions or additions, go undetected, and the faulty cell is able to complete cell cycle. Occasional mutations do not do much harm, but in large numbers, the results can be catastrophic. Mutations can effect nearby and distant cells alike, eventually leading to cancer (Alberts, 2014).

Unfortunately, for pediatric hepatoblastoma (HB), most cases are erratic, and the molecular mechanism of the disease is still largely unknown. What is known, though, is that there are several mutated genes and proteins that appear to somehow be connected to the development of HB (Dong, 2014; Yamada, 2004). Some of these abnormalities include Beckwith-Weidman Syndrome, which is caused by mutations and uniparental disomy (two copies from one parent) of chromosome 11; and mutations in the ß-catenin gene (CTNNB1.) Mutations in CTNNB1 suggest an important role in the wingless/integrated (Wnt) signaling pathway in the origination of HB (Finegold, 2007).

The Wnt signaling pathway is involved in the G2 and mitosis phases of the cell cycle, regulating early embryonic development and embryonic stem cells, as well as homeostasis of adult tissues and adult stem cells (Davidson, 2010). Wnt is a secreted ligand (molecule that binds to a macromolecule) that binds to its receptor at the cell membrane. This leads to the stabilization of cytoplasmic CTNNB1 protein by inhibiting the process of CTNNB1 degradation. CTNNB1 is then able to enter the nucleus and activate other Wnt-regulated genes (Chen, 2008). The Wnt signaling pathway as a whole is regulated by the Cdks, which are supposed to regulate cell proliferation. It has been found that CDK14 is most correlated with the Wnt pathway. When the Cdks upregulate the Wnt pathway via upregulation of CTNNB1, cell proliferation becomes impaired, leading to an abundance of mutated cells (Davidson, 2010).

It has also been investigated whether or not long non-coding RNA (lncRNA) has a role in the genesis of HB. These lncRNAs target and differentiate certain messenger RNAs (mRNA), which convey genetic information to the ribosomes (site of protein translation.) A large number of these lncRNAs and mRNAs have been found to sometimes be dysregulated in HB. One lncRNA in HB tissues, TCONS-00014512, was found to be located near endothelial cell-specific molecule 1 (ESM1.) The function of ESM1 is to promote cell survival, cell cycle progression, tumor cell migration and invasion, and tumor angiogenesis (the formation and differentiation of blood vessels in tumors.) If there were a dysregulation, and ESM1 was therefore differently expressed, it could potentially lead to the development of cancer. Furthermore, the regulation of p53 is at least partly controlled by the lncRNA maternally expressed 3 (MEG3,) which is commonly altered in cases of HB. Although little research has been done in this area, continuation of such research may lead to a better understanding of HB (Dong, 2014).

All of these genetic abnormalities can potentially affect the prognosis. Depending on the prognosis, and how positive it is, a treatment plan can be set up to better treat the believed genesis of the tumor.

Treatment

Numerous factors need to be taken into account when deciding which option is best for the treatment of HB. The patient’s age, overall health, medical history, extent of disease, personal tolerance for specific medications, and expected course of the disease, for example, must all be considered when determining the course of treatment. Currently, the most common options include complete or partial surgical removal of the tumor, chemotherapy, and liver transplant. These therapies are almost always used together to increase the success of treatment (Hepatoblastoma, n.d.).

The effectiveness of surgically removing the tumor can be influenced by what type of cells the cancer has invaded. In cases where the cancer has infected solely fetal liver tissues (referred to as PFH,) there tends to be a higher probability of long-term effectiveness of the treatment. In a study done by the Children’s Oncology Group, it was found that in patients with only stage 1 infection of PFH, the five-year cancer-free rate following tumor removal and three subsequent doses of chemotherapy was 100% (Malogolowkin, 2011). For other HBs though, the majority of cases undergo preoperative chemotherapy. During the initial course of chemotherapy, it is highly important to devise a plan for the best surgical option. If a pulmonary metastasis (secondary tumor) is present, it often leads to a poor prognosis. However, a large number of patients have been reported to achieve long-term survival after the metastasis has been removed. This is good news, seeing as pulmonary metastasis used to mean the patients needed a liver transplant (Hishiki, 2013).

Chemotherapy works to shrink the tumor by damaging the control center of the cell in charge of cell division, thereby killing cells that are in the process of dividing. Most often, chemotherapy is administered through injection into the bloodstream, intravenous infusion, tablets, or capsules (How chemotherapy works, 2015). Cisplatin, a chemotherapeutic drug, is often used in treating HB and is often used in conjunction with surgical treatment to increased likelihood of success (Liu, 2015). Up to 85% of originally inoperable tumors become operable after going through chemotherapy (Khaderi, 2014). In a retrospective study of 63 patients receiving regimen C5V (cisplatin, fluorouracil, and vincristine,) only 24.5% of the patients had tumor recurrence after pre and post-operative therapy. The stage and invasiveness of the cancer plays a large role in how effective the chemotherapy treatment will be, as well as how successful the tumor resection surgery was (Liu, 2015). Unfortunately, a fair amount of patients develop a resistance to chemotherapy treatment. In HB patients, chemotherapy seems to increase to the production in survivin, a protein that inhibits apoptosis by inhibiting caspase activity (Olie, 2000; Uehara, 2013). This can obviously be quite detrimental to the treatment process.

When chemotherapy and surgical removal of the tumor(s) prove unsuccessful or implausible, a liver transplant is the next step in treatment. Liver transplants should immediately be considered in cases where the cancer is multifocal (more than one site of infection,) and located closely to, or has invaded major vessels. When a transplant becomes necessary, it is most effective when used along with pre and post-operative chemotherapy, just like surgical removal is (Khaderi, 2014). A review of liver transplants performed on HB patients from 1988 to 2010 showed a 5-year survival rate of more than 75% of the children operated on, with only a 16% tumor recurrence (Ravaioli, 2014).

Due to HB’s difficulty to treat, new treatments are constantly being sought out. Recently, it has been found that, in addition to cisplatin based chemotherapy, the use of sepantronium bromide (YM155,) which is a survivin inhibitor, enhanced the sensitivity of cisplatin to HB cells that had become resistant to the chemotherapy. This combined therapy significantly decreased HB cell proliferation and formation, and even induced cell death better than either therapies alone are capable of. This is a promising step in the future of hepatoblastomic treatment (Yu, 2015).

HB can be aggressive and difficult to treat. Although huge improvements have been made in treatments in the last few decades, there is still a long way to go in improving the prognosis of this cancer. Luckily, there are many doctors working to find new and innovative methods to help find a cure.

Opinion

This rare childhood cancer’s main quality that makes it unique is the role of the Wnt pathway in the cell cycle leading to cancer development. As mentioned before, the Wnt signaling pathway involved in the G2 and mitosis phases is regulated by the Cdks, which regulate cell proliferation. Interestingly, although p53 does not seem to be as largely correlated with HB, p53 anti-differentiation functions in embryonic stem cells of the mouse were found to deregulate the Wnt pathway. Mutations of the p53 gene are often found as the main instigator for cancer, but although it does seemingly play somewhat into HB development, the deregulation of the Wnt signaling pathway is more looked to in the development of HB. (Wnt Signaling and Cancer, Stem Cell or Cell Cycle, n.d.).

Using this information and doing more research can help formulate new hypotheses of potential future treatments. One possible future treatment could be targeted gene therapy. Gene therapy works by introducing new genetic material into cells to make up for mutated genes or to make a beneficial protein. If a mutated gene causes a necessary protein to be dysfunctional or missing altogether, gene therapy could potentially introduce a normal copy of that gene to restore the function of the protein (How does gene therapy work? 2015). If inhibitor proteins that could target CTNNB1 were found, they could potentially be used to inhibit the upregulation of the Wnt pathway. Cdks involved in regulation could also be good candidates for targeting therapy (Yamada, 2004). If these genes and proteins could be targeted and effectively down regulated in the cancerous cells, it would lead to less cell proliferations, and therefore less mutated cells wreaking havoc on the body.

Long non-coding RNAs could also potentially be an interesting area to look at for treatment. Unfortunately, this area of gene expression is still largely unclear (Alberts, 2014, p. 284). Depending on how lncRNAs are found to function, and determining which specific lncRNAs are involved, researchers could upregulate or downregulate the production of these lncRNAs using gene therapy in attempt to shrink the HB tumors.

Pediatric hepatoblastoma’s aggressiveness and rarity make it a difficult cancer to study. Many possible links to its development have been found, but with its erraticism, it can be hard to pinpoint a certain marker to focus on. The links that have been found to occur in a larger amount of patients have already lead to potential new treatment therapies. Hopefully, with the ongoing research being performed on current patients, a step can be made toward the cure or more effective treatment of hepatoblastoma.

Biblical Integration

When there is a life crisis to be dealt with, people often turn to or from God. Some people become angry with God and accuse him of being unjust: “if God created everything, then he must have created cancer, right? Why would he do such a horrible thing?” This is a difficult question with a difficult answer that many people try to avoid all together. Cancer has robbed millions of families of their loved ones, causing them great pain and grief. When situation like this arise, people must turn to the Bible for answers.

Disease first became a possibility when Adam and Eve ate from the tree of knowledge of good and evil. God said to them “…cursed is the ground because of you; in pain you shall eat of it all the days of your life; thorns and thistles it shall bring forth for you;…for you are dust, and to dust you shall return.” (Genesis 3:17-18, English Standard Version). Because mankind sinned, all mankind was cursed, eternal life was taken, and pain and suffering entered the world. Because of sin, bodies decay. Because bodies decay, cells begin to not function properly, foreign organisms infect the body, and people get sick. All diseases and means of death are possible, cancer included. The second law of thermodynamics states that natural processes (such as cell division) tend to move toward a state of greater disorder (Giancoli, 2014, p. 426). This leads to the conclusion that the sin of mankind created the possibility for disease. Although God allows this to happen because of man’s sin, he does not outright cause diseases such as cancer.

That leads to the question of how Christians should react to cancer. Is cancer punishment for an unrepented sin or, is it simply part of life? People are in a constant state of slowly deteriorating and becoming one step closer to death, cancer is just one pathway of the death that everyone experiences. Matthew 5:45 says, “…For he makes his sun rise on the evil and on the good, and sends rain on the just and on the unjust.” Good things happen to bad people; bad things happen to good people. Although the direct consequences of one’s actions may be unfavorable, God does not give anyone a gold star for following every rule, nor does he send a storm cloud over people’s heads when they mess up. Likewise, God does not punish people by giving them cancer. Everyone has calamity in some form or another in their life, and when they, or a loved one experience such difficulties, it should be a pathway for strengthening their faith and building their relationship with God.

The Bible actually gives an example of dealing with weaknesses in this way in 2 Corinthians, chapter 12. Paul is telling the readers that although life is giving them thorns and hard ships, they must be used for good (2 Corinthians 12:7). God tells Paul, “My grace is sufficient for you, for my power is made perfect in weakness (2 Corinthians 12:9).” Bodily ailments are the perfect opportunity to glorify God’s strength, and for God to work in the person’s soul. That is why God allows it.

A diagnosis of cancer is something no one wants to hear, but when they do, people must know how to react to it as Christians. With God being an omnipresent, all-powerful God that he is, the human mind is not capable of comprehending his awesomeness, or why he allows the things he allows. Romans 11:33 says “Oh, the depth of the riches and wisdom and knowledge of God! How unsearchable are his judgments and how inscrutable his ways!”

If the Christian themselves are diagnosed with cancer, they should rely on God for strength through such a difficult time, knowing that there is a purpose, and death is not something that should be feared. If an unbeliever is diagnosed, Christians should shower them with as much love and support for that person as they can, and try to show the power and love of God through support. People must remain as positive as they can during hardships. After all, “a joyful heart is good medicine (Proverbs 17:22).”