Cell Cycle Rules Aren’t for Fools

Posted by Joseph Herdy on December 15, 2022 in Cancer, Epigenetics, genetics | Leave a comment

Our great gamble as individuals composed of trillions of cells is that every cell is going to get along together and play by the rules. Our gut cells wake up and slay the nutrient uptake game every day, our retina cells are on top of processing incoming light, and even the humble cells in our nailbed keep fertile ground coming up for the next manicure. However, there’s a classic example of a cell not playing by the rules: cancer. For a huge variety of reasons, some of our cells ditch the normal playbook and decide they’re gonna do things their way, often with lethal consequences especially when left unaddressed. The nervous system is no exception, and here we’ll explore some of the causes and consequences of cancerous transformation that might occur in our brain.

What Causes Cancers in Your Cranium?

First a little background on what goes wrong with cancer. Cancers are fundamentally a loss of control of the cell cycle, that is, the series of events that takes place in a cell before it divides into two daughter cells. This is a highly regulated process that dates back billions of years, and there’s a lot of built-in guardrails to stop cells from dividing without the proper cues and signals. The process of actually completing a cell division is called mitosis, where one cell becomes two. When one division will suffice it’s best to keep it that way, and most cells in our body sit in interphase, not dividing but preparing for possible divisions on the horizon. In cancers, there’s often some damage or a gap in the guardrails that can cause a cell to tip the scales and slip from interphase into mitosis when they shouldn’t. Left unchecked, a runaway cell speeding through the cell cycle divides too much and becomes a cancer that can form masses of cells i.e. tumors. 

Although our brains have billions of neurons, interestingly, they’re very rarely the source of brain tumors. This is because neurons are thought to be completely post-mitotic, meaning they have left the cell cycle and won’t divide again for their entire life. This tight regulation of the cell cycle is likely the reason why neuroblastomas (tumors arising from neurons) are so rare, neurons just can’t divide! What is the reason for this? Why are neurons so resistant to cancerous transformation? One of the major drivers of cancer in many cell types is mutations in certain “risky” genes, the so called oncogenes, that when mutated are more likely to cause a cell to lose control of the cell cycle. Interestingly, neurons experience a large amount of DNA damage and mutations during our lives but these rarely manifest in cancer like in other cells, so there’s something other than just mutation prevention that protects neurons [1].

Guardrails in Your Cells

A lot of work has been done to find the source of this protection. One proposed control is the organization of the neuronal genome in the nucleus. Our DNA is like a stretchy book, and sometimes if we move certain portions of it physically closer to others, it can change how it is read. Cancer cells often rely on this and contort our DNA into unusual shapes to avoid proper regulation. Some proteins that are specifically found in neurons, like NeuN, have significant DNA binding properties and are a component of the nuclear membrane, where they stabilize the DNA into structures that are more resistant to being stretched and help maintain genetic integrity [2]. 

Another powerful restriction on neuronal cancer seems to be that cellular division itself is actually lethal to neurons, which was discovered almost by accident. Neurons wont grow in the lab, and so investigators have to continually get fresh ones from a (once) living (mouse) brain, what a pain! In the 90s, a group tried to get around this limitation by overexpressing a powerful oncogene in neurons, hoping to make a neuronal cell line that could be propagated indefinitely [3]. However, instead of finding a plate full of happy neurons, they discovered that all the cells overexpressing the oncogene had died! Follow-up work determined that re-entry into the cell cycle somehow triggers enough DNA damage to be lethal to neurons, but not other cell types. The basis of this lethality is still a matter of hot debate, and could be due to the proteins that neurons have available to synthesize new DNA. 

Another important feature is the age of the cancer patient. Unfortunately, although neuroblastomas are rare in adults, they are by far the most common form of cancer in infants (https://www.cancer.org/cancer/neuroblastoma/about/key-statistics.html). Because children’s nerve tissues are still growing and developing rapidly, they don’t have the same types of safeguards against cancer that protect us later in life. Most neuroblastomas in infants typically start in the sympathetic nervous system: the part of the nervous system that controls blood pressure, heart rate, and digestion. One of the challenging aspects of neuroblastomas in children is that symptom presentations can be very diverse depending on where the tumor started, and there’s also wide differences in the aggressiveness of the tumors. Thankfully, most neuroblastomas have excellent clinical outcomes when detected early, and scientists continue to make advances in treating the high risk forms [4].

Nefarious Neurons

Although neurons themselves are resistant to cancer, they can still play a detrimental role in the progression of tumors. Nerve/cancer interactions have been shown to support cancer development and progression. Tumors need access to lots of blood and nutrients to help them grow, and they can sometimes hijack nearby nerve cells by releasing certain chemicals, called neurotrophic factors that entice nerves to enter the tumor. Once there, these nerves can trigger a process called angiogenesis, which is the growth of new blood vessels, to deliver blood and nutrients to the growing tumor. 

Nerves don’t only help tumors grow, they can also help them spread. To spread, cancer cells must depart from the primary tumor and escape to other parts of the body. In some tumors, stress molecules and other proteins released by neurons can directly promote the invasion of cancer cells to new areas. Further, the same neuropeptides that promote angiogenesis can promote the permeability of the blood vessels, allowing cancer cells to escape and wreak havoc elsewhere in the body. 

Although these are major challenges, scientists are also taking advantage of some tumors’ reliance on neurons to treat them. One recent strategy is a targeted delivery of an anesthetic to tumors [5]. The anesthetic blocks nerve signaling to the tumor by inhibiting synapse interactions between tumor and nerve cells  The nanoparticles target the important anesthetic to the tumor and reduce the off-target effects of injecting an anesthetic throughout the body.  This strategy has already been shown to help the prognosis in an aggressive form of breast cancer.

No two cancers are the same, and therefore the relationship between neurons and cancer is quite complex. On the one hand, neurons themselves are largely off the hook for forming tumors, yet we know that they can often play less-than-helpful roles in cancer progression. As the field of neurooncology grows, however, we are beginning to understand where things go wrong and how to intervene. While a cancer-free world is still far off on the horizon, we are slowly learning the rules of the game and strategies to keep everyone working together on the same playbook.

1. Aranda-Anzaldo A. (2012). The post-mitotic state in neurons correlates with a stable nuclear higher-order structure. Communicative & integrative biology, 5(2), 134–139. https://doi.org/10.4161/cib.18761
2. Hutchison, C. J., & Worman, H. J. (2004). A-type lamins: guardians of the soma?. Nature cell biology, 6(11), 1062–1067. https://doi.org/10.1038/ncb1104-1062
3. Feddersen, R. M., Ehlenfeldt, R., Yunis, W. S., Clark, H. B., & Orr, H. T. (1992). Disrupted cerebellar cortical development and progressive degeneration of Purkinje cells in SV40 T antigen transgenic mice. Neuron, 9(5), 955–966. https://doi.org/10.1016/0896-6273(92)90247-b
4. Pudela C, Balyasny S, Applebaum MA. Nervous system: Embryonal tumors: Neuroblastoma. Atlas Genet Cytogenet Oncol Haematol. 2020 Jul;24(7):284-290. doi: 10.4267/2042/70771. PMID: 32296467; PMCID: PMC7158874.
5. Kaduri M, Sela M, Kagan S, Poley M, Abumanhal-Masarweh H, Mora-Raimundo P, Ouro A, Dahan N, Hershkovitz D, Shklover J, Shainsky-Roitman J, Buganim Y, Schroeder A. Targeting neurons in the tumor microenvironment with bupivacaine nanoparticles reduces breast cancer progression and metastases. Sci Adv. 2021 Oct 8;7(41):eabj5435. doi: 10.1126/sciadv.abj5435. Epub 2021 Oct 6. PMID: 34613777; PMCID: PMC8494443.
6. Editorial contributions from Jordan Coburn