BioQuakes

AP Biology class blog for discussing current research in Biology

Tag: oncogenes

Researchers Discover Hacking Enzymes as New Cancer Treatment

We all know that mutations occurring in the synthesis of our cells lead to cancer, whether that be via ultraviolet light radiation, the inhalation of cigarette smoke over a long period of time, or otherwise. But how do these mutations actually occur, and if modern science knows that much, why can’t scientists step in before the mutation occurs in the cell and stop the creation of a cancerous one altogether? While the answer to this is evidently easier said than done, researchers such as Szymon Barcawz, Rahul Bhomick, Malgorzata Clausen, Marisa Dinis, Masato Kanemaki, Ying Liu, Katrine Lundgaard, and Wei Wu have found a way to limit the success of cancer-yielding cell mutations. 

In this study titled, ‘Mitotic DNA Synthesis in Response to Replication Stress Requires Sequential Action of DNA Polymerases Zeta and Delta in Human Cells,’ researchers studied the replication process of cells, also known as mitosis, in human body cells (all human cells except gametes, sex cells). In order to understand the study fully, a few biological concepts should be covered first; For starters, the activation of the oncogene in relation to developing cancer. ‘Oncogene’ is simply a term for a mutated cell which turns cancerous. The activation of such creates disorder to cells going through mitosis called DNA replication stress, the name of which essentially reveals its effect: when genetic material is being synthesized under these conditions, it is extremely difficult for the mitotic cell to correctly replicate, causing faulty, under-replicated DNA regions (UDRs) to be built. Since DNA replication is completed in the S phase of interphase, which technically is before the commencement of mitosis in a cell; enough genetic material needs to be available for the cell to split in order for it to be replicated. Therefore, if UDRs are going to occur in a cell, they are created during this time. 

However, our cells have developed clever adaptations to attempt to fight this type of cellular mistake. The strategy includes performing “‘unscheduled’ DNA synthesis in mitosis (termed MiDAS) that serves to rescue under-replicated” genetic material (Barcawz et al.). In studying this cellular defense mechanism, these researchers have discovered how exactly cells make up for a faulty S phase (the phase which copies DNA during mitosis) utilizing DNA gap-filling mechanisms (REV1 and Pol ζ) and DNA polymerases (group of enzymes) whose sole purpose is to replicate unfinished genomes (Pol δ). The study’s main goal, however, was to reveal which of these polymerases was the most crucial in the “rescuing” of under-developed genetic material, which were not, and which were not really necessary at all. 

The researchers were most interested in studying POLDI (a subunit of  Pol δ), REV 1, and REV 3 / REV 7 (both subunits of Pol ζ).  These are all different polymerases whose main job is to “[promote] the bypass of damaged DNA sites” (Barcawz et al.). Each one works to solve a different issue within DNA replication that could lead to a mutation. For example, a TLS polymerase called Pol ζ4 is better at “bypassing bulky regions” of genetic material than the others (Barcawz et al.); this can be defined as Pol ζ4’s ‘role.’  

A crucial realization in this study was that the polymerases Pol ζ and Pol δ may actually be switching roles at some point within the rescuing process by switching their subunits, which we defined earlier as POLDI, and REV3 / REV 7. But, this still doesn’t answer the question of whether or not all the aforementioned polymerases are essential in the process of fixing mutations in the copying of genetic material during mitosis. 

The study at hand was successful at answering this question. It found that POLDI, REV1, and REV 3 are crucial to MiDAS, while REV7 is not at all. Additionally, it was discovered that POLDI and REV1 colocalize with another substance (FANCD2) in mitosis, which reveals how they both indeed play a role in the ‘rescue’ of under-replicated regions” (Barcawz et al.).

However, something unexpected about REV1 was also discovered. While it was found to be useful in mending UDRs in conjunction with POLDI and FANCD2, it actually does more harm than good: When REV1 was removed from the rescuing process in a situation where all the cell’s defense mechanisms failed at stopping the synthesis of a cancer cell, cancer cells were much less likely to survive in the human body. This suggests that it is very possible for a new and effective way to treat cancer to be the inhibition of the presence of REV1 polymerase. 

In the coming years, if the inhibition of REV1 is found to be possible and turns out to be a promising way of preventing cancer cells from surviving in the body, we could be looking at a groundbreaking advancement to modern medicine and the world of cancer treatment as we know it changing forever.

Cancer cells

Real image of cancer cell under a microscope.

Hot dogs, Fries, and Chicken Nuggets Aren’t Good For Me?

Although foods such as soft drinks, chips, and breakfast cereals have been normalized as good meals, these foods are ultra-processed, and new research shows just how dangerous these foods can be. A recent study from the Imperial School of Public Health in London provides new and convincing evidence that ultra-processed foods lead to cancer, especially ovarian and breast cancer.

Now, you may be wondering how one develops cancer. One develops cancer when cells divide uncontrollably. These uncontrollable divisions begin due to a mutation in genes, sections of DNA. Proto-Oncogenes are genes involved in normal cell growth; these genes cause cells to divide. A mutation in a single allele of a proto-oncogene causes a protein to be produced that will exponentially increase the rate of cell division. Tumor suppressor genes are involved in the stopping of cell growth. When both alleles in a tumor suppressor gene are mutated, it leads to an inability to stop cell division.

Cancer

So, how does ultra-processed food cause mutations in your genes? It is believed that these foods can eventually lead to the mutation of alleles in proto-oncogenes and/or tumor suppressor genes. All ultra-processed foods share the commonality of being created by substances extracted from foods: Fats, starches, added sugars, and hydrogenated fats. A diet consisting of these types of food can lead someone to develop type II diabetes. People with type II diabetes are twice as likely to develop liver or pancreatic cancer. These people also have a much higher risk of developing bladder, colon, or breast cancer. When someone has a lot of excess fat around vital organs, it makes it very easy for cancer cells to get the nutrition they need to keep uncontrollably dividing. The fat from glucose is what the cancer cells need to continue to divide; cancer cells are known to metabolize glucose at 200x the normal rate. When one has Type II diabetes, they have increased blood sugar. If the cancer cells have access to blood flow, the increased blood sugar gives the cancer cells even more nutrients to keep dividing. Even though one can not say for sure, it seems increasingly apparent that avoiding ultra-processed foods is best for your health. So, the next time you want a snack, maybe an apple and a glass of water are your best bet.

 

Customizing Cancer?

Oncologists are moving toward a future in which cancer treatment is customizable and specific to each patient. This is achieved through genomic testing. Medical News Today: Pancreatic cancer splits into four types, says genome study

As genes differ from person to person, the information from genomic testing is unique to each. This speaks to what we’ve learned recently in bio class about how cellular mutations cause cancer. Changes to the DNA of a cell, specifically to genes that control the cell cycle, could result in oncogenes. But, I digress. The drawback of this type of treatment is that oncologists are met with so much information that it becomes not useful,  making the treatments less personal than they should be.

CHALLENGING GENETICS

The reason for this is due to the inability to identify which test will be most useful for each patient. When genetic data is obtained, what it means for the patient isn’t exactly clear. The example given in an article by Andrew Ip states that “several inhibitors of the enzyme anaplastic lymphoma kinase (ALK) have proven effective in treating lymphoma, non-small cell lung cancer, and neuroblastoma, while other findings suggest one of the inhibitors can treat pediatric oncology patients”. Although information was found from research specifically for ALK, it appears that much more is affected by these inhibitors making it less “personalized” than intended. 

Another reason as to why genomic testing is so difficult is accessibility. It can be difficult to get the treatments to patients due to health insurance limitations. In another instance, according to Andrew, “oncologists in community settings … had difficulty handling tumor samples, faced long turnaround times for laboratory tests, and had limited access to targeted therapies. To make it more difficult, next-generation sequencing results are often provided as a pdf, which cannot be digitally integrated with a patient’s electronic health records”. It appears altogether that oncologists are hindered by the lack of seamless integration of genomic testing into daily scenarios.

THERE IS HOPE

Although it appears that oncologists are overwhelmed, there is progress being made to support them. 

At the Hackensack Meridian Health John Theurer Cancer Center, where Andrew practices oncology, genomic testing was put into action. An ill patient had two separate biopsies done, and the findings of both contrasted each other greatly. One specified that the cancer identified was incurable, while the genomic sequencing depicted the cancer as curable. The patient was treated with chemotherapy and made quick improvement. 

The Genomic Testing Cooperative joined with Hackensack Meridian Health to implement an “in-house genomic profiling center”. As stated in Andrews article, the center “analyzes 434 genes for solid tumors, searching for DNA and RNA mutations and chromosomal structural abnormalities. For blood cancers, the service generates a 177 gene panel hematology profile”.

This isn’t all. A new database to which will aid oncologists in using the genomic results, cancer types, cancer medicines and patient outcomes is being built there as well.

FUTURE ADVANCES

In order to fully take advantage of genomic sequencing, companies are turning toward artificial intelligence. The goal is for AI to be able to use information from genomics, drug trials, patient demographics, and past scientific research to provide its own efficient course of action. This is called a clinical decision support system or CDS. IBM Watson was to be a CDS but did not suffice.

Until then oncologists take what Andrew describes as a “holistic approach to care”. This involves working with multidisciplinary teams made up of radiologists, pathologists, medical oncologists, radiation oncologists, and surgeons. Altogether they are known as molecular tumor boards. It’s fascinating to see just how much goes into making cancer care especially personalized to each patient.

The Role of Metabolism and Epigenetics in Cancer Development

Cancer most commonly is defined as a “perpetuating mass of dystregulated cells growing in an uncontrolled manner”, however the meaning can be further related to epigenetics, for they appear to be very much interconnected.  Another definition of cancer goes on to note this relationship as the “dynamic genetic and epigenetic alterations that contribute to cancer initiation and progress.” Recent research shows that if epigenetics is disrupted, it might switch to oncogenes or shut down tumor suppressors. Either way, this would lead to the development of tumor cells that would cause cancer. We are already aware of the fact that chemical modification affecting the packaging of our DNA can switch genes on and off. The first time that became aware of an epigenetic code, we learned that that code chemically labels active or inactive genetic information. The focus of epigenetics is on the change caused by the modification of gene expression, not the alteration of the code itself. With recent discoveries through research on epigenetics and its relation to cancer, we learned that there must be a balance of “writers” and “erasers” for the cells. Recent data has shown that methyltransferase EZH2 is an epigenetic writer that is hyperactivated in many cancers, specifically melanomas and lymphomas. This recent research also shows KDM3A (member of the jumonji histone lysine demthylase family) as an epigenetic eraser. KDM3A fulfills an oncogenic role by activating a network of tumor promoting genes. Epigonomic changes also allow tumor cells to evade the immune system so that these cells can thrive and divide without the disruption of the immune system. Ultimately, there are two potential pathways that epigenomic regulators can cause cancer. The first is the result of too much epigenetic activation, which can lead to oncogenes. The second is too much epigenetic protection that conversely blocks tumor suppressor genes. DNA hypermethylation causes the silencing of tumor suppressor genes.

Both of these methods would lead to the development of cancer. Epigenetic regulation involves methods including histone regulation, DNA methylation, and changes in noncoding RNAs such as miRNAs. One of the challenges of studying cancer and researching possible vulnverabilities in pathways is that they are often disrupted by epigenetics. The recent studies also have shown that there are close ties between epigenomic (analysis of global epigenetic changes across many genes) changes and metabolites, or human cellular chemistry. Metabolites initiate, target, or maintain epigenetic factors with the transcriptional complex, and cooperation with them metabolites can target, amplify or mute these coded responses. Since the fields of both epigenetics and metabolism are still developing a great deal, there is hope that these insights with regards to cancer and regulating gene expression to prevent the development of cancer will allow for more precision in targeting cancer, specifically when existing methods of therapy fail to work sufficiently.

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