Why are some cancers so difficult to treat?

By Madeleine Eaton

Cancer is a disease of uncontrolled cell division, leading to the formation of a tumour within the body. This is caused by both environmental and genetic factors and develops over time, eventually invading secondary tissues in the body in a process called metastasis.1 Cancer deaths account for a quarter of deaths in the UK alone (165,000 per year).2 Therefore, it is essential that effective treatments are developed to improve this high mortality rate. However, cancer has many characteristics that make treatment difficult, including its genomic instability, its ability to become resistant to one or many potential treatments, and the existence of phenotypically distinct cancer stem cells driving tumorigenesis.

The genomic instability of cancer cells contributes to the difficulty in treatment. Due to the constant uncontrolled division of cancer cells and an inability to repair damaged DNA, cancer cells develop significant numbers of mutations over their lifetime. One mutation type is translocation, where a portion of one chromosome breaks off and reattaches to a different chromosome. This can cause hundreds of different point mutations within a single cancer cell, and the sheer number of mutations makes identification of which mutations caused the cancer and which are simply harmless by-products difficult (1). Without this knowledge, appropriate treatments cannot be devised. Genetic mutations also cause drug resistance in cancer cells, which poses significant problems for treatment. Anticancer drug resistance follows the principles of Darwinian selection, as the drugs impose a selection pressure favouring those cells acquire mutations conferring drug resistance. Traditional treatments of cancer cells include surgery, cytotoxic drugs, or radiation. However, if some cells carry a mutation allowing them to survive treatment, the tumour may be drastically reduced by the initial treatment but be completely regenerated by the resistant cells later on.3 A clinical example is chronic myelogenous leukaemia (CML), a cancer of the bone marrow typically caused by a reciprocal chromosomal translocation known as the Philadelphia chromosome.4 This mutation causes a hyperactive protein kinase that maintains cell proliferation/resists apoptosis. The current treatment is a drug preventing the fusion protein BCR-ABL from binding ATP and therefore from signalling to its downstream target proteins, reducing its cancer proliferating activity.5 However, this drug provides a selection pressure to the tumour which leads to some cancer cells randomly developing mutations that allow them to resist the drug. This cell strain will proliferate preferentially so that the entire tumour eventually becomes resistant. Furthermore, multidrug resistance has been observed in some cancers, in which expression of P-glycoprotein and multidrug resistance associated protein allows the efflux of the cytotoxic drug.6 The development of resistance against multiple potential treatments further complicates treatment, as there may be no potential drugs left that tumour cells are susceptible to. A major challenge is to effectively eradicate the entire tumour without drug resistance developing, and this greatly increases the difficulty in successfully treating cancer.

One major reason for cancer development that also contributes to treatment difficulty is the deregulation of the apoptosis, a type of programmed cell death where damaged cells are removed to prevent organism injury. The process is normally tightly regulated; however, many cancer cells have developed mutations allowing them to proliferate despite genomic damage. Apoptosis is carried out by caspases, specific proteases leading to the formation of apoptotic bodies and eventual cell death.1 Caspase activation is complex, but one of the key oncogenes identified in apoptosis deregulation is the p53 gene. This gene is mutated in many human cancers, and it has been shown that those with Li-Fraumeni syndrome who carry germline mutations in the gene often develop multiple different cancers throughout their lives, supporting the idea that mutation here is key in cancer development.3 In normal conditions, the p53 gene helps activate apoptosis in response to cellular stress or damage by acting as a transcription factor for around 500 different genes. It upregulates transcription of proapoptotic genes, downregulates transcription of antiapoptotic genes, indirectly causes cytochrome c release triggering the intrinsic apoptotic pathway, and expresses death receptors that promote the extrinsic apoptotic pathway.3 The ability of p53 to activate both intra and extracellular apoptotic pathways shows how crucial it is for this process. Mutation here leads to deregulation of the pathway in cancer cells. Knock-out p53 cells are resistant to attempted drug induced apoptosis, but it has also been shown that gain of function p53 mutants can resist chemotherapy drugs. In particular, engineered p53 mutants expressed high levels of dUTPase genes and developed resistance to the cancer drug 5-fluorouracil.3 Apoptosis avoidance is a defining characteristic of cancer, as it allows cells to accumulate mutations and genetic damage but continue proliferating as well as to resist treatment. An additional implication of cancer cell resistance to apoptosis in response to DNA damage during chemotherapy is that the treatment itself becomes a carcinogen. Without the apoptosis pathway, cells continue to accumulate new mutations, and this can lead to therapy- related leukaemia where the treatment itself causes a new cancer.3

The existence of cancer stem cells that have differing properties to their progenitor tumour cells means that eradication of the entire tumour is difficult. It has been theorized that tumour growth is driven by a subset of tumour stem cells, which have properties similar to normal stem cells like self-renewal and the ability to differentiate into phenotypically distinct cells composing the tumour’s bulk.4 Experimental evidence for their existence comes from the fact that not all cancer cells lead to secondary tumour formation in other tissues during metastasis. Cancer stem cells are more likely to develop into malignant secondary tumours through the process of metastasis as compared to other cells. Al-Hajj et al. demonstrated that solid tumours contained a small distinct cell population with the ability to generate new tumours when implanted into mice. These cancer-initiating cells were the only cells continually forming tumours when implanted and expressed cell surface markers similar to normal stem cells. The tumours generated from cancer stem cells were composed of both cells with and without these markers, even though they all originated from the same clonal cell.10 This shows how tumour stem cells are responsible for generating the phenotypical diversity of tumour cells. Tumour stem cells are also more resistant to typical treatments compared to normal cells, making them difficult to eradicate. Cancer stem cells may hold innate resistance due to their effective DNA repair, decreased apoptosis, and expression of multidrug transporter proteins that pump drugs out.9 In the example of CML drug resistance given previously, tumour regrowth after treatment is caused by cancer stem cells with Philadelphia chromosome mutations that resist treatment.10 This shows how tumour eradication is complicated by the inherent properties of cancer stem cells. In order to fully cure the cancer, all stem cells must be eliminated along with their offspring, however because the stem cells are more resistant to typical treatments, it is difficult to design a treatment that will be effective against both tumour cell types.

With all these elements in mind, it is evident that cancer treatment is a complex issue. Its diversity, genomic instability, and resistance to both the apoptotic pathway and drugs make treatment incredibly difficult. Additionally, the recent discovery of cancer stem cells that are predominantly responsible for tumour proliferation but are also resistant to many traditional forms of therapy further complicate the problem. Treatments must be designed to be patient specific and must be able to eliminate all cancer cells, including stem cells, while considering the possibility of drug resistance, making cancer one of the most difficult diseases to treat. 

References:

1) Alberts et al. (2015) Molecular Biology of the Cell. Sixth edition. United States, Garland Science.

2) Cancer Mortality Statistics. Available

from: https://www.cancerresearchuk.org/health-professional/cancer- statistics/mortality#:~:text=Cancer%20mortality%20for%20all%20cancers%20combi ned&text=Cancer%20accounts%20for%20more%20than,88%2C900%20cancer%20d eaths%20in%202017.

3) Lauren Pecorino. (2008) Molecular Biology of Cancer. Second edition. United States, Oxford University Press.

4) William L. Farrar. (2010) Cancer Stem Cells. United State of America, Cambridge University Press.

5) Zhi-Jie Kang, Yu-Fei Liu, et al. (2016) The Philadelphia chromosome in leukemogenesis. Chinese Journal of Cancer. 35 (48), Available

from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896164/#:~:text=The%20tru ncated%20chromosome%2022%20that,but%20also%20disrupts%20genomic%20sta bility. Available from: doi: 10.1186/s40880-016-0108-0.

6) Cancer multidrug resistance. (2000) Nature Biotechnology. 18 (10), IT18-IT20. Available from: https://doi.org/10.1038/80051. Available from: doi: 10.1038/80051.

7) Brandon J Aubrey, Gemma L Kelly, Ana Janic, Marco J Herold & Andreas Strasser. (2018) How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? Nature. 25 Available

from: https://www.nature.com/articles/cdd2017169. Available from:

doi: https://doi.org/10.1038/cdd.2017.169.

8) Muhammad Al-Hajj, Max S. Wicha, Adalberto Benito-Hernandez, Sean J. Morrison & Michael F. Clarke. (2003) Prospective identification of tumorigenic breast cancer cells. Proceedings of the National Academy of Sciences – PNAS. 100 (7), 3983-3988. Available from: https://search.datacite.org/works/10.1073/pnas.0530291100. Available from: doi: 10.1073/pnas.0530291100.

9) Dean, M., Fojo, T. & Bates, S. (2005) Tumour stem cells and drug resistance. Nature Reviews Cancer. 5 (4), 275-284. Available from: https://doi.org/10.1038/nrc1590. Available from: doi: 10.1038/nrc1590.

10) Sajib Chakraborty and Taibur Rahman. (2012) The Difficulties in Cancer

Treatment. US National Library of Medicine; National Institutes of Health. Available from: doi: 10.3332/ecancer.2012.ed16.

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