Changes In Protein Glycosylation In Cancer

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02 Nov 2017

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Abstract

Breast cancer is a heterogenous disease which remains the most common cancer in women worldwide. Despite advances in diagnosis and in treatment, metastatic disease kills a significant proportion of those with the disease. New treatments to reduce morbidity and mortality are required as is the development of diagnostic and prognostic biomarkers. Developments in the understanding of the biology of the disease are a necessary requirement in order to further these developments. Metastatic spread in breast cancer is the major cause of progression, relapse and death. Two families of molecules, the selectins and the integrins, have been identified and demonstrated to be involved in cell to cell adhesion and establishment of secondary tumours, However, an understanding of the exact nature of cell to cell interactions in metastasis is still in progress. Additionally, aberrant glycosylation of proteins is known to play a significant role in cancer disease and progression and represents a novel biomarker for disease management.

Introduction

In 2002, cancer incidence worldwide was reported at around eleven million new cases and an associated seven million deaths (Kamangar et al, 2006). The most common disease types found were breast, lung, prostate, liver, cervix, esophagus and gastrointestinal cancers. This represented an increase in cancer incidence from ten million new cases and six million deaths in 2000, demonstrating that cancer levels continued to increase (Parkin, 2004). Prevalence, incidence and mortality correlated to individuals’ risk factors such as diet, physical activity and smoking rates and also to inherent factors such as age and genetics (Souhami & Tobias, 2008). Additional factors such as cultural or religious practices, the availability of healthcare, environmental exposures and the socioeconomic environment further complicate the geographical management of cancer. Any successful plan to reduce cancer disparities between populations requires to take all of these factors into account. Bray et al (2012) used the Human Development Index (HDI) to examine changing patterns of cancer and, by extrapolating incidence until 2030, predict a continuing increase in all cancer cases to reach over 22 million.

Breast cancer at this time remains worldwide the most common cancer in women, although cervical cancer is more common in low HDI areas, and the incidence of breast cancer in medium and high HDI areas is increasing. The GLOBOCAN Project tracks incidence of breast cancer globally and currently their figures demonstrate that the highest incident levels are in Western Europe and the lowest in Eastern Africa. Mortality rates in breast cancer are lower than might be expected given the incidence because of advances in treatment - however, it remains the most frequent cause of cancer death in women from both the developed and the developing worlds (Globocan, 2008). GLOBOCAN statistics for cancer in women in the UK show that the incidence of cancer remains the highest for breast cancer at around 84 cases per 100,000 and with a mortality rate of around 9 per 100,000. This mortality rate is only surpassed by that for lung cancer for which the incidence rate is significantly lower.

Breast cancer is considered to originate as a local disease which can metastasise to the lymph nodes and to other distant sites in the body, particularly the lung, liver and bones and less usually the brain. However, it has been suggested that breast cancer should be considered as a cancer which is inherently systemic (Weigelt et al, 2005). Effective therapeutic management of the primary tumour in early disease is now possible due to the introduction of mammography and the use of systemic adjuvant therapy. As around 15% of individuals develop distant metastases within three years of diagnosis, systemic chemotherapy is standardly utilised due to the inaccuracy of predicting whether metastasis will develop and therefore many patients who would not develop further lesions receive toxic treatment which they do not require. However, mortality rates correlate with metastasis and around 40% of patients still progress or relapse and die due to metastatic cancer (EBCTCG, 2005). Survival rate is also dependent on age. Those aged less than 50 years and those older than 50 years have increases in their 15 year survival rates of 10% and 3% respectively following adjuvant therapy. Additionally metastases can occur greater than 10 years after diagnosis (Hellman & Harris, 2000). Diagnosis and/or treatment for (potential) metastasis remains extremely important in both managing the disease and in reducing morbidity and mortality but advances in treatment and in the development of prognostic markers remain a requirement.

Cancer biology

The development of cancer or carcinogenesis is a cellular pathway which involves genetic changes and a variety of factors, including oncogenes and tumour suppressor genes, both of which influence cell growth and development. Genetic changes are mainly only evident in malignant cells and are usually acquired, that is they are not inherited via the germline – although this can occur in a minority of instances where individuals are predisposed to developing particular cancers. Polymorphisms (inherited gene mutations) do have a role in increasing cancer risk, to a greater or lesser extent, dependent on the mutation in question.

Oncogenes are genes in which alterations cause gain-of-function effects whilst tumor suppressor genes are genes in which alterations cause loss-of-function effects (Osborne et al, 2004). These alterations express in a malignant phenotype through a series of complex changes and interactions which is reflected in the fact that breast cancer is a heterogenous disease – there is a large inter- and intra-tumour variability in both genotype and phenotype.

Many oncogenes have been identified in vitro in breast cancer but few have been demonstrated to play a substantive role in vivo. Activation of oncogenes can occur via a number of mechanisms. Gene amplification results in over expression of the gene product, an example being the HER-2 protein (Gutierrez & Schiff, 2011) which occurs in around 20% of primary breast cancers. HER2 is a membrane receptor tyrosine kinase whose activation renders cells proliferative and resistant to apoptosis signals. HER2 is only one of many proteins involved in the HER2/Neu cascade whose role remains to be fully characterised. Other HER family genes, such as the one encoding epidermal growth factor receptor (EGFR or HER1), a member of the HER gene family is also expressed in breast cancer but to a much lesser extent than HER2 (Witton et al, 2003) and is possibly associated with a poor clinical outcome.

The c-myc oncogene, a transcriptional regulator which encodes a nuclear phosphoprotein, is involved in cell proliferation, differentiation, and apoptosis and has been found to be overexpressed in 15%–25% of breast tumors (Nass & Dickson, 1997). Like EGFR is it thought to result in a poorer outcome and is associated with aggressive disease – however, it remains unclear as to whether its overexpression alone is sufficient to instigate disease.

Cyclin-dependent kinases (CDKs) such as cyclin D1 and cyclin E are members of a group of proteins which regulate the cell cycle (Sutherland & Musgrove, 2009). Cyclin D1 is overexpressed in 40%–50% of invasive breast cancers whilst cyclin E is overexpressed in around 20%-30 of breast cancers. Elevated levels of cyclin D1 and cyclin E expression are both associated with increased cell proliferation (and for cyclin D1, estrogen receptor (ER) positive cancer) but cell cycle control is more affected when cyclin E is overexpressed.

Activation can also occur via point mutation which results in functional enhancement of the encoded protein – however this mechanism has not been documented in breast cancer. Chromosomal translocation, where a fusion of genes is transcribed as an enhanced fusion protein, represents another activation mechanism.

Loss of function of tumor suppressor genes promotes malignancy as these genes usually negatively regulate growth or other cellular functions such as adhesion which in turn can impact on the invasiveness and/or metastatic ability of cancer cells. Mutations in tumor suppressor genes can occur through inheritance (in a minority of cases) or via sporadic mutation. Tumour cells usually have a mutation in one allele and a deletion of the remaining allele. Alternatively, there may be a mutation in another gene that affects the function or expression of the tumour suppressor gene. Inherited mutations in tumor suppressor genes have been useful in diagnosis of breast cancer.

Mutations in the gene p53, which encodes a protein with multiple functions, including regulation of cell division, are common to around 50% of all cancers and in 20%–30% of breast cancers (Lacroix et al, 2006). Aberrant p53 expression is associated with poor prognosis, is linked to negative ER status and is recognised as a strong predictor of outcome, particularly as it increases relapse risk by around a third. P53 is a category II prognostic marker in breast cancer (Thor et al, 1992)

p27 and Skp2 are negative regulators of the cell cycle. The former is a cyclin-dependent protein kinase inhibitors (CKI). Decreased levels of p27 is a strong predictor of breast cancer outcome and correlates to shorter overall survival and shorter time to progression, independent of tumor grade. Skp2 is a S-phase kinase-associated protein which degrades, in an ubiquitin-mediated manner, p27. Skp2 is thought to be preferentially overexpressed in ER− and HER-2− breast cancer, or "basal phenotype" breast cancer (Eroles et al, 2012).

The BRCA-1 and BRCA-2 genes, which are involved in DNA repair, are significant examples of inherited predisposition genes in breast (and ovarian) cancer and represent a leading cause of mutation, genomic instability (Welcsh & King, 2001) and are tumour suppressor genes. Around 5% of breast cancers in women under 40 years are related to BRCA-1 mutations of which more than 200 have been described; this figure rises to greater than 90% where there is a family history of breast cancer (or ovarian cancer). The lifetime risk of developing breast cancer when carrying the BRCA-1 mutation is very high - greater than 50% at age 50 years and rising to over 70% by age 70 years.

A large number of mutations in BRCA-2 have also been described – more than 100. Most mutations in both genes result in premature truncation of the protein and as is the case with BRCA-1, random mutation is rare. Also, as is the case with BRCA-1, the lifetime risk for developing breast is very high for those with BRCA-2 mutations and both mutations are strongly associated with higher tumour grade.

A number of other tumour suppressor genes including BRCA-3, PTEN which encodes a negative regulator phosphatase, cell cycle checkpoint serine threonine kinase (CHK2), the ATM gene involved in DNA repair and the retinoblastoma (Rb) gene, which was the first tumor suppressor to be described, are likely to be implicated in breast cancer carciogenesis.

Post-translational modification of proteins, for example via phosphorylation and glycosylation, has been implicated in cancer development and progression (Krueger &. and Srivastava, 2006).

The metastatic process

Cancer metastasis is a multistep process which begins with development of a primary tumour, spread of cancer cells to local tissue, distribution of the cells throughout the body by the systemic circulation to secondary sites, via capillary leakage, and ultimately the establishment of secondary tumours at different site(s) in the body (King, ?). This has been described as the ‘seed and soil’ hypothesis (Fidler, 2003). Cell to cell adhesion of tumour cells with endothelial cells throughout the body is necessary for the spread of malignancy. Additionally, tumor cells interact directly with and adhere to other cell types such as platelets and leukocytes, which enables metastatic cells to become established. As cell to cell interactions are essential for metastatic spread, targeting of the molecules involved represents a potentially use novel therapeutic target.

A group of cell adhesion molecules are considered to be significantly involved in the metastatis pathway (Bendas & Borsig, 2012). Two major families of adhesins have been identified and shown to be significant in metastatis and these are denoted as the selectins and the integrins (Läubli & Borsig, 2012; Desgrosellier & Cheresh, 2010).

The selectins, P-, E-, and L-, are vascular cell adhesion molecules involved in a variety of physiological process including inflammation, immune response, and hemostasis. They are able to bind to a variety of molecules including mucins, glycolipids and carbohydrates. Epithelial cells are covered by mucins, high-molecular-weight molecules with a large proportion of O-linked glycans which are known to change during the process of malignant transformation (Kannagin et al, 2004) and which has been linked to cancer progression and poor prognosis. Selectins also bind to cancer cells.

The integrins are large complex transmembrane glycoproteins which mediate cell adhesion and directly bind extracellular matrix (ECM) components, such as fibronectin or collagen and which are found ubiquitously on tumor cells and on blood components. They are therefore likely to be implicated in metastasis.

Cell membrane proteins also have a major role in cell adhesion and cell to cell communication as membrane receptors are overexpressed in cancer cells. As a consequence they are a potentially valuable target for cancer cell therapy (Kampen, 2011).

Glycosylation in cancer

Glycosylation, the addition of a sugar molecule (monosaccharides and oligosaccharides) to a protein, which is catalysed by a glycosyl transferase, is a post translational modification. N-linked and O-linked glycosylation represent the two main types. In N-linked, the sugar units are attached via the amide nitrogen of an asparagine residue whilst in O-linked, the sugar units are attached via the hydroxyl group of serine, threonine, hydroxylysine or hydroxyproline residues.

Protein glycosylation has been recognised as a factor in cancer pathogenesis for many years (Brooks et al, 2002). Mass spectrometry has been used to detail glycosylation changes in cancer cells and to characterise its role in disease development and progression (Mechref. Et al, 2012) in a variety of cancer types. Aberrant glycosylation is associated with aberrant expression of enzymes including glycosyltransferase and glycosidases which subsequently results in the synthesis of glycoprotiens with errors in their glycan structures. These errors in structure allows glycoproteins to be utilised as potential biomarkers in cancer and many biomarkers used in the clinic are glycoproteins. Additionally, particular alterations in glycan structures are associated with particular cancers and this specificity can be used in proteomic technologies in the development of new diagnostic, and potentially prognostic, biomarkers (Meany & Chan). S-linkage to cysteine and C-linkage to tryptophan are examples of other glycosidic linkages.

Glycosylation of proteins does not occur in a random manner – specific sugars are attached to particular polypeptides and it is thought that the glycosyltransferase for each polypeptide recognises specific amino acid sequence motifs. The motif for N-linked glycosylation is known (-Asn-Xaa-Ser/Thr/Cys where Xaa is not proline) but the motif for There is no known motif for O-linked glycosylationhas not yet been characterised although it occurs in serine, threonine and proline rich sequences. Protein glycosylation is complex – glycosylation may be full or partial and more than one glycan structure can occur at any one site. The glycosylation process is process directly controlled by glycosyltransferases and indirectly by hormones such as thyrotropin and retinol.

Conclusion

Breast cancer has been traditionally classified by staging using the TNM system (tumor, nodes, metastases) which takes into account the tumor size, the status of lymph nodes, and the presence of distant metastasis. Recent advances have led to additional classification based on gene expression (Eroles et al, 2012). One model, the intrinsic subtype model, employs six classification groups or subtypes which are luminal A, luminal B, HER2-enriched, basal-like, normal breast and claudin-low. Although not yet standardised and therefore not ready for use in the clinic they have led to a more in-depth understanding of breast tumor biology. Clinical trials are required to define how and if they may lead to an improvement in breast cancer management, via improved tumour classification and improved response prediction, and should aid in the development of novel treatments. Additionally, novel biomarkers for both diagnosis and prognosis are under development which is necessary to reduce the mortality levels associated with metastasis in breast cancer. Cancer-specific glycosylated proteins represent a new potential biomarker in future disease management.



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