Public Understanding of Science- The common characteristics of cancer

Public Understanding of Science- The common characteristics of cancer

By Shane Houston, PhD Candidate Queen’s University Belfast

Cancer is an age old adversary of the human race. This out-of-control growth of abnormal cells has been a shadow over human health throughout history. Some of the earliest evidence of cancer stretches back to Egypt and the time of the pharaohs [1].

As time has marched on, so has our understanding of the disease, a field which came to be known as Oncology [1]. Early attempts at treating the disease most often involved surgical removal, followed by the hope the disease would not return [1]. Invariably it did. The current trend of research in cancer therapy is now leaning towards personalized medicine, a treatment approach based on the genetic profile of each patient’s individual cancer [2]. As a consequence, common characteristics shared by all cancers have been metaphorically “placed on the shelf”. This article aims to revisit these characteristics, in hopes of inciting fresh research in an already exciting field.

Weird Metabolism

During the 1930’s, a German physiologist and medical doctor by the name of Otto Heinrich Warburg noticed a peculiar characteristic of cancer cells. He noted that many cancer cells switch from using oxygen to metabolise glucose (aerobic respiration) to the anaerobic metabolism of glucose (also known as fermentation), even in the presence of oxygen!

He also noticed that, linked to this anaerobic metabolism of glucose; cancer cells produce large amounts of lactic acid [3]. Warburg went on to suggest that cancer was in some way caused by this strange metabolism. Furthermore, he observed that under low oxygen conditions a selective pressure favoring cells intrinsically possessing strong fermentation capabilities was decidedly at work [3]. This, he postulated, was a shared characteristic of all cancers to a greater or lesser degree. The phenomenon was aptly coined the “Warburg Effect” and its biochemistry and molecular mechanisms have seen a resurgence in research interest over the last decade or so [4].

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Figure.1- Image showing sequential reduction in size from a villus in the intestine through to the ultrastructure of their microvilli using light and electron microscopy [6].

Fluffy Membranes

All cells possess a plasma membrane, the cells double bilayer barrier to its external environment that maintains the correct intracellular balance of ions, metabolites, H2O and CO2 [5]. These plasma membranes possess a multitude of finger-like projections, called microvilli, that serve functional roles including increasing absorptive surface area in epithelial cells in the intestine, cell-to-cell adhesion and storing plasma membrane prior to cell division amongst others, as seen in Fig.1 [5,6].

However, these “fluffy cell fences” have been shown to increase in number and length along with cancer cell proliferation across a range of cancer subtypes and studies [7, 8, 9]. This second shared cancer characteristic seems to serve a multitude of functions. Recent studies have shown that glioma cells, a type of brain cancer, can keep cytotoxic-T cells, the salient sentinels of the immune system, at a non-lethal distance using their overexpressed microvilli [10]. This facilitates their continued survival and potential spread to other tissues and organs, a phenomenon known as metastasis [11].

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Figure.2 – Integral glycoprotein embedded in the cell membrane. Arrows indicate sialic acid residues (left). Terminal sialic acid residue of a glycan attached via a glycosidic bond to the most common penultimate glycan residue, galactose (right) [15]

Strange Sugars

The plasma membranes and microvilli mentioned earlier are not barren wastelands on the outside of the cell.

Speckled all over the outer membrane of mammalian cells is a structure known as the glycocalyx,[12,13] a composite collection of proteins and lipids linked to different sugar residues, also known as glycans[6,14]. The most prevalent sugar residue amongst this molecular forest is sialic acid, usually found linked to a penultimate galactose residue as seen in Fig.2 [14, 15]. These 9-carbon negatively charged (monosaccharide) sugars are attached to the terminal ends of almost all cell surface glycans in various different linkage configurations through sugar-sugar glycosidic bonds [16].

They are important as antigens in the immune system through to pathogenic virulence and in cancer [6].

These monosaccharides, as well as others, are best discussed with reference to their “partners in crime” known as lectins and defined as, “..proteins that preferentially recognize and bind carbohydrate complexes protruding from glycolipids and glycoproteins” [17]. The detrimental dynamics between this overexpression of cancer cell surface sialic acids and their specific lectins is one of the main molecular routes of transport and inversion of normal cellular functions cancer cells utlilize [17].

Under The Radar

Sialic acids are present on all cells and are markers of “self” to the immune system [14].Therefore, up-regulation of sialic acid production in most cancer cells results in the immunoevasion, and suppression, of immune effector cells through various means [15].

Sialic acids and metastatic potential- a travelling band

Sialic acid levels have also been linked to increased mobility of cancer cells in a range of studies. A recent study in the journal Oncology Reports showed that increased sialic acid residues of the α2,3 linkage conformation in breast cancer were associated with increased metastatic potential[20]. In another recent study it was shown that the level of sialic acid expression on intestinal epithelial cells surface was linked to those cells metastatic potential as well! [21]

Consequently, heavily glycosylated cancer cells can preferentially invade tissues and continue their insidious spread throughout the body.

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Figure.3 In the presence of activating ligands and absence of inhibitory ligands on the target cell, NK cells are activated to release cytotoxic effectors and cytokines. Localization of Siglecs to the site of activation halts cellular activation [16].

Future Outlooks

The re-visitation of these shared cancer characteristics is an exciting prospect, with the potential to identify new common characteristics. From the historically long, but patchy, “breadcrumb” trail of papers in this area, there is a clear conclusion to be made; more work needs to be carried out in therapeutically probing these common vulnerabilities. The potential of finding a proverbial “Golden Bullet” to cancer, through one or more of these mechanisms, has the potential to save thousands, if not millions, of lives and money currently lost to this disease.

References

American Cancer Society (2014) The History of Cancer, Available at: http://www.cancer.org/cancer/cancerbasics/thehist... (Accessed: 18/10/2014).

Gonzalez de Castro, D., Clarke, P.A., Al-Lazikani, B., Workman, P. (2013) ‘Personalized Cancer Medicine: Molecular Diagnostics, Predictive Biomarkers, and Drug Resistance’, Nature, 93(3), pp. 252-259.

Warberg, O. (1956) ‘On the Origin of Cancer Cells’, Science, 123(3191), pp. 309-314

Gatenby, R.A. and Gillies, R.J. (2004) ‘Why do cancers have high aerobic glycolysis?’, Nature Reviews Cancer, 4(11), pp. 891-899.

Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K. and Walter, P. (2008)Molecular Biology of the Cell, 5th edn., 270 Madison Avenue, New York NY10016, USA: Garland Science.

Varki, A., Cummings, R., Esko, J., Freeze, H., Hart, G. and Marth J. (1999) Essentials of Glycobiology, Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press

Ren, J., Hamada, J.I., Okada, F., Takeichi, N., Morikawa, K., Hosokawa, M. and Kobayashi, H (1990) ‘Correlation between the presence of Microvilli and the Growth or Metastatic Potential of Tumor Cells’, Japanese Journal of Cancer Research, 81(9), pp. 920-926.

Yan, W., Chen, Y., Yao, Y., Zhang, H. and Wang, T. (2013) ‘Increased invasion and tumorigenicity capacity of CD44+/CD24- Breast Cancer MCF7 cells in vitro and in nude mice’, Cancer Cell International, 13(62), pp. 1-7

Vic, P., Vignon, F., Derocq, D. and Rochefort, H. (1982) ‘Effect of Estradiol on the Ultrastructure of the MCF7 Human Breast Cancer Cells in Culture’, Cancer Research, 42(2), pp. 667-673.

Zaguia, F. and Schneider, R. (2011) ‘Microvilli expressed on glioma cells keep cytotoxic cells at a distance’, Cancer Biology & Therapy, 11(1), pp. 1-3.

Schulz, W.A. (2005) Molecular Biology of Human Cancers, USA: Springer Science.

Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K. and Walter, P. (2008)Molecular Biology of the Cell, 5th edn., 270 Madison Avenue, New York NY10016, USA: Garland Science.

Alphonsus, C.S. and Rodseth, R.N. (2014) ‘The endothelial glycocalyx: a review of the vascular barrier’, Anaesthesia, 69(7), pp. 777-784.

Varki, N.M. and Varki, A. (2007) ‘Diversity in cell surface sialic acid presentations:’, Laboratory Investigations, 87(9), pp. 851-857.

Professor Vincent Rancaniello (2009) Influenza virus attachment to cells, Available at: http://www.virology.ws/2009/05/04/influenza-virus... (Accessed: 20/10/2014).

Büll, C., Stoel, M.A., Den Brok, M.H. and Adema, G.J. (2014) ‘Sialic Acids Sweeten a Tumor’s Life’, Cancer Research, 74(12), pp. 3199-3204.

Ghazarian, H., Idoni, B. and Oppenheimer, S.B. (2011) ‘A glycobiology review: carbohydrates, lectins, and implications in cancer therapeutics’, Acta histochemica, 113(3), pp. 236-247

Macauley, M.S., Crocker, P.R., and Paulson, J.C (2014) ‘Siglec-mediated regulation of immune cell function in disease’, Nature Reviews Immunology, 14(10), pp. 653-666.

Hudak, J.E., Canham, S.M. and Bertozzi, C.R. (2014) ‘Glycocalyx engineering reveals a Siglec-based mechanism for NK cell immunoevasion’, Nature Chemical Biology, 10(1), pp. 69-75.

Cui, H., Lin, Y., Yue, L., Zhao, X. and Liu J. (2011) ‘Differential expression of the α2,3-sialic acid residues in breast cancer is associated with metastatic potential’, Oncology Reports, 25(5), pp. 1365-1371 .

Redondo, P.A.G., Nakamura, C.G., Souza, W. and Diaz, J.A.M. (2004) ‘Differential Expression of Sialic Acid and N-acetylgalactosamine Residues on the Cell Surface of Intestinal Epithelial Cells According to Normal or Metastatic Potential’, Journal of Histochemistry & Cytochemistry, 52(5), pp. 629-640

10th Jul 2020 Shane Houston, PhD Candidate Queen’s University Belfast

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