By Esha Kulkarni
There have been various cutting edge novel technologies that are being developed to help detect various types of cancers. Indeed, detection of cancer is the first step in providing treatment to patients. Recently, scientists are making use of key “biomarkers”, i.e, molecules that are persistent in tumor populations, to help mark and detect cells that display cancer characteristics, allowing for early detection and treatment for patients. Cancer detection is not only complex in terms of finding biomarkers, but utilizing cost-effective and non-invasive methods to detect cancer is also difficult and in demand as there is currently a rise in cancer patients and mortality in the world. Additionally, early detection of cancer is needed to provide personalized care and help tackle the disease faster. However, a concrete understanding of cancer progression, key pathways, its characteristics are crucial to first and foremost detect and differentiate a tumor cell from non-cancerous cell.
In cancer biology, cancer cells are cells that display six main characteristics that are essential in the transformation of a normal cell to a malignant tumor cell. These six main characteristics are: evading apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals, tissue invasion and metastasis, limitless replicative potential and sustained angiogenesis.1 These biological hallmarks of cancer have been extensively studied over the past few decades to help target pathways for drug design as well as identify biomarkers associated with these hallmarks to detect tumour cells. Recent progress in the last few years have allowed scientists to refine the existing hallmarks by introducing another emerging hallmark of cancer: cancer metabolism.1
Uncontrolled cell proliferation is the main feature of the disease. However, due to the increased cell proliferative potential, cancer cells have also shown to exhibit alterations in their energy metabolism in order to help sustain and provide energy for the rapid division of cells. Cancer cells are shown to have unique metabolic requirements to cope up with their growth needs, including increased bioenergetics and biosynthesis and alteration in the redox belance2. Due to the high proliferative rate of cancer cells they tend to outgrow the blood supply which provides the cells with nutrients and oxygen, generating a hypoxic tumor environment. To meet these high metabolic demands, cancer cells undergo metabolic reprogramming by switching to a glycolytic state. Glycolytic state is when cells break down glucose to pyruvate generating ATP. Although glycolysis provides a lower yield of ATP, it is more efficient and provides rapid source of ATP even under presence of low oxygen. However, it was also observed that cancer cells also use glycolysis as its main source of energy even under normal oxygen levels, hence the term “aerobic glycolysis” or the Warburg effect. Scientists investigated why Warburg effect is deemed advantageous for cancer cells and discovered that glycolysis generates large pools of carbon intermediates and metabolites that can be siphoned to biosynthesize ribose and deoxyribose (DNA and RNA components), lipids and amino acids that are essential metabolites needed for rapid growth of tumor cells.3 Therefore cancer cells have altered energy metabolism compared to normal cells, another way to distinguish normal cells vs cancer cells.
Altered metabolic pathways of cancer cells release biomarkers called volatile organic compounds (VOCs) at higher concentrations than normal pathways, some examples being: aldehydes, acetone, ketones, ethane, etc. VOCs are released into the bloodstream and excreted through breath and other bodily fluids such as sweat and saliva. Since cost-efficient, rapid, non-invasive technologies for cancer detection are lacking, detection of VOCs is currently at the forefront for rapid cancer diagnostic technologies.4 Breath and sweat test devices are being developed and used by biotech companies to measure exact metabolite concentrations, but is there an easier and quicker way to provide an early diagnosis of cancer? Interestingly, the adored canine creatures, dogs, could be the next generation of cancer detectors.
Dogs can sniff scents from miles away. They are known to have an incredibly intricate olfactory system similar to humans. However, it is much more sensitive as they can detect VOCs at even extremely low concentrations starting from 1:1 trillion VOCs, comparable to a single drop of liquid in 20-olympic sized pools!5,6 This is because they have 220 million scent receptors whereas humans have only 5 million, which is why dogs have been trained over the years to hunt, search explosives, drugs and now possibly even identify diseases.6Multiple studies have shown dogs to be reliable detectors of early signs of cancer especially Labradors, retrievers and German Shepherds. They can sniff exogenous VOCs in breath, urine, sweat and tissue samples. In a study, training of ordinary household dogs enabled them to detect lung cancer with 99% accuracy and breast cancer with 88%. They were also able to distinguish the various stages of cancer.7However, it is unknown whether there is a “signature “scent of cancer cells that sniffer dogs detect due to possible the presence of cancer-specific VOCs. Researchers concluded that lung cancer cells can release certain lung -cancer specific VOCs such as 2-methyl pentane but also release VOCs that are in higher concentration than normal cells. The signature odor of the normal vs cancer samples detected by sniffer dogs might be associated to the quantity and quality of a mixture of VOCs rather than cancer-specific VOC that is released.8
Overall, sniffer dogs can help in early detection and diagnosis of cancer providing early patient care. Since most types of cancers release similar kinds of VOCs with only some that are cancer specific, canine non-invasive detection could potentially lead to false diagnosis of the type of cancer as they are unable to detect cancer specific VOCs. Nevertheless, to further exploit the advantages of this non-invasive approach and the highly sensitive olfactory system of dogs, scientists are developing electrical nose devices that mimic the olfactory system of dogs and can be always worn by patients as gadgets. Indeed, incorporating AI technology for VOC detection by understanding dog anatomy could possibly revolutionize cancer diagnosis and detection.
References:
- Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell.2011;144(5):646–74.
- DeBerardinis RJ, Chandel NS. Fundamentals of Cancer metabolism. Science Advances.2016;2(5).
- Martínez-Reyes I, Chandel NS. Cancer metabolism: Looking forward. Nature Reviews Cancer. 2021;21(10):669–80.
- Khatib M, Haick H. Sensors for volatile organic compounds. ACS Nano.2022;16(5):7080–115.
- Feil C, Staib F, Berger MR, Stein T, Schmidtmann I, Forster A, et al. Sniffer dogs can identify lung cancer patients from breath and urine samples. BMC Cancer. 2021;21(1).
- Rozenbaum M. The science of Sniffs: Disease smelling dogs [Internet]. Understanding Animal Research. 2020 [cited 2022Nov7]. Available from: https://www.understandinganimalresearch.org.uk/news/the-science-of-sniffs-disease smelling-dogs
- McCulloch M, Jezierski T, Broffman M, Hubbard A, Turner K, Janecki T. Diagnostic accuracy of canine scent detection in early- and late-stage lung and breast cancers. Integrative Cancer Therapies. 2006;5(1):30–9.
- Buszewski B, Ligor T, Jezierski T, Wenda-Piesik A, Walczak M, Rudnicka J. Identification of volatile lung cancer markers by gas chromatography–mass spectrometry: Comparison with discrimination by canines. Analytical and Bioanalytical Chemistry. 2012;404(1):141–6.
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