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Receptor tyrosine kinases (RTKs) play an important role in a variety of cellular processes including growth, motility, differentiation, and metabolism. As such, dysregulation of RTK signaling leads to an assortment of human diseases, most notably, cancers. Recent large-scale genomic studies have revealed the presence of various alterations in the genes encoding RTKs such as EGFR, HER2/ErbB2, and MET, amongst many others. Abnormal RTK activation in human cancers is mediated by four principal mechanisms: gain-of-function mutations, genomic amplification, chromosomal rearrangements, and / or autocrine activation. In this manuscript, we review the processes whereby RTKs are activated under normal physiological conditions and discuss several mechanisms whereby RTKs can be aberrantly activated in human cancers. Understanding of these mechanisms has important implications for selection of anti-cancer therapies.

Nature (2014) doi:10.1038/nature13506

Cell membranes are covered with sugar-conjugated proteins. New findings suggest that the physical properties of this coating, which is more pronounced in cancer cells, regulate cell survival during tumour spread.

The cell membrane serves as a signalling interface that allows cells to exchange information with their environment. It is constructed from lipids and contains both transmembrane and lipid-tethered proteins, which can be further modified through the covalent addition of sugars to build glycoproteins. Cancer cells frequently have higher levels of glycoproteins, such as mucin-1 (refs 1,2,3), than do healthy cells, and individual glycoproteins can transduce environmental signals that directly promote malignancy. However, glycoproteins also collectively organize into a glycocalyx. In a paper published on Nature’s website today, Paszek et al.4 show how the physical properties of this coating regulate the clustering of cell-surface receptors and thereby affect intracellular signalling in ways that can contribute to cancer metastasis.

The authors demonstrate that the thickness of the glycocalyx is a crucial determinant of the spatial and temporal features of receptor–ligand interactions. Specifically, they find that the thick glycocalyx of cancer cells serves as a ‘kinetic trap’, generating regions on the cell surface where the likelihood of receptor–ligand interactions is increased, driving receptor clustering (Fig. 1). Integrins are transmembrane receptors that bind extracellular matrix (ECM) proteins and are key interpreters and integrators of both the biochemical composition and the mechanical properties of the extracellular space5, 6. Paszek and colleagues reveal that cells with a thick glycocalyx are more efficient at receiving cell-survival signals through integrins, owing to the kinetic-trap properties of the glycocalyx. This may facilitate metastatic spread by enabling cancer cells to survive in the varied tissue and fluid environments they must traverse to colonize distant organs.

Clinical Chemistry January 2013 vol. 59 no. 1 147-157

BACKGROUND: Protein cancer biomarkers serve multiple clinical purposes, both early and late, during disease progression. The search for new and better biomarkers has become an integral component of contemporary cancer research. However, the number of new biomarkers cleared by the US Food and Drug Administration has declined substantially over the last 10 years, raising concerns regarding the efficiency of the biomarker-development pipeline.

CONTENT: We describe different clinical uses of cancer biomarkers and their performance requirements. We also present examples of protein cancer biomarkers currently in clinical use and their limitations. The major barriers that candidate biomarkers need to overcome to reach the clinic are addressed. Finally, the long and arduous journey of a protein cancer biomarker from the bench to the clinic is outlined with an example.

SUMMARY: The journey of a protein biomarker from the bench to the clinic is long and challenging. Every step needs to be meticulously planned and executed to succeed. The history of clinically useful biomarkers suggests that at least a decade is required for the transition of a marker from the bench to the bedside. Therefore, it may be too early to expect that the new technological advances will catalyze the anticipated biomarker revolution any time soon.

Mol Biol Rep. 2012 Aug;39(8):8483-90. Epub 2012 Jun 15.

Abstract

The cumulative lifetime risk for the development of colorectal cancer in the general population is 6 %. In many cases, early detection by fecal occult blood test is limited regarding sensitivity. Therefore, there is an urgent need for improved diagnostic tests in colorectal cancer. The recent development of high-throughput molecular analytic techniques should allow the rapid evaluation of new diagnostic markers. However, researchers are faced with an overwhelming number of potential markers form numerous colorectal cancer protein expression profiling studies. To address the challenge, we have carried out a comprehensive systematic review of colorectal cancer biomarkers from 13 published studies that compared the protein expression profiles of colorectal cancer and normal tissues. A protein ranking system that considers the number of comparisons in agreement, total sample sizes, average fold-change and direction of differential expression was devised. We observed that some proteins were consistently reported by multiple studies as differentially expressed with a statistically significant frequency (P < 0.05) in cancer versus normal tissues comparison. Our systematic review method identified proteins that were consistently reported as differentially expressed. A review of the top four candidates revealed proteins described previously as having diagnostic value as well as novel candidate biomarkers. These candidates should help to develop a panel of biomarkers with sufficient sensitivity and specificity for the diagnosis of colorectal cancer in a clinical setting.

Discov Med. 2011 Jun;11(61):537-50.

Abstract

Age is the most important risk factor for tumorigenesis. More than 60% of new cancers and more than 70% of cancer deaths occur in elderly subjects >65 years. The immune system plays an important role in the battle of the host against cancer development. Deleterious alterations occur to the immune response with aging, termed immunosenescence. It is tempting to speculate that this waning immune response contributes to the higher incidence of cancer, but robust data on this important topic are few and far between. This review is devoted to discussing state of the art knowledge on the relationship between immunosenescence and cancer. Emerging understanding of the aging process at the molecular level is viewed from the perspective of this increased tumorigenesis. We also consider some of the most recent means to intervene in the modulation of immunosenescence to increase the ability of the immune system to fight against tumors. Future research will unravel new aspects of the immune response against tumors which will be modulable to decrease the burden of cancer in elderly individuals.

Clinical Chemistry. 2009;55:1471-1483

Background: DNA methylation is a highly characterized epigenetic modification of the human genome that is implicated in cancer. The altered DNA methylation patterns found in cancer cells include not only global hypomethylation but also discrete hypermethylation of specific genes. In particular, numerous tumor suppressor genes undergo epigenetic silencing because of hypermethylated promoter regions. Some of these genes are considered promising DNA methylation biomarkers for early cancer diagnostics, and some have been shown to be valuable for predicting prognosis or the response to therapy.
Content: PCR-based methods that use sodium bisulfite–treated DNA as a template are generally accepted as the most analytically sensitive and specific techniques for analyzing DNA methylation at single loci. A number of new methods, such as methylation-specific fluorescent amplicon generation (MS-FLAG), methylation-sensitive high-resolution melting (MS-HRM), and sensitive melting analysis after real-time methylation-specific PCR (SMART-MSP), now complement the traditional PCR-based methods and promise to be valuable diagnostic tools. In particular, the HRM technique shows great potential as a diagnostic tool because of its closed-tube format and cost-effectiveness.

Summary: Numerous traditional and new PCR-based methods have been developed for detecting DNA methylation at single loci. All have characteristic advantages and disadvantages, particularly with regard to use in clinical settings.

Türk Klinik Biyokimya Derg 2010; 8(1): 35-42

Transforming Growth Factor- beta (TGF-beta) doku homeostazının sürdürülmesinde önemli rol oynamaktadır. TGFbeta sinyalizasyon yolunun bozulması kanserde büyük önem taşımaktadır. Proapoptotik etkisi ile, ayrıca epitelyal hücre proliferasyonu ve inflamatuar cevabını da baskılayarak TGFbeta bir tümör supresörü gibi davranır. Tümör hücrelerinde, sitoplazmik kolu elemanlarında mutasyon sonucu TGFbeta yolunun yavaşlaması, ya da TGFbeta’nin sitostatik etkilerinin baskılanması ile (nükleer kol), TGFbeta’nın antitumoral etkileri bertaraf edilir. Tümör oluşumu sırasında TGFbeta antiproliferatif etkilerini kaybeder ve onkojenik özellikler kazanır. Bu derlemede kanserde TGFbeta’ün tümör süpresif fonksiyonlarının buzulmasına neden olan mekanizmalar gözden geçirilmiştir.

Prof. Dr. Semra KOÇTÜRK

Apoptoz fizyolojik şartlardaki çok hücreli organizmalarda, hem gelişim sırasında hem de gelişimini tamamlamış organizmaların homeostazının sağlanmasında istenmeyen hücrelerin yok edilmesi için evrimleşmiş karmaşık bir mekanizmadır. Apoptoz veya Tip I hücre ölümü, oldukça sıkı kontrol mekanizması ile hücre sayısını kontrol eden ve hasarlı hücrelerin ortadan kaldırılmasını sağlayan mekanizmadır. Bu nedenle tümör hücrelerinin çoğalmasının baskılanmasında çok önemli rol almaktadır. Apoptoz mekanizması potansiyel zararlı hücrelerin yok edilmesi görevini üstlendiğinden pek çok hastalık ile de yakından ilişkilidir. Aşırı apoptoz, fazla hücre kaybı nedeniyle iskemik ve nörodejeneratif hastalıklara sebep olurken, yetersiz apoptoz otoimmün hastalıklara ve kansere neden olmaktadır. Fizyolojik süreçte büyüme faktörlerinin hücreye ulaşamaması veya hücrenin oksidatif stres, hipoksi, iyonize radyasyon, UV ya da ilaç uygulamaları gibi farklı etkenlerin etkisinde kalması sonucunda oluşan hasarlı hücrelerin yok edilebilmesi için apoptotik mekanizma tetiklenmektedir. Morfolojik olarak apoptoz süreci; plazma membranının tomurcuklanması, membranda bulunan fosfotidil serin kalıntılarının membranın dış yüzeyine yönelmesi, hücre büzüşmesi, kromatin kondenzasyonu ve hücre içeriğinin çoklu membran kaplı parçacıklar halinde dağılarak komşu hücreler ve fagositler tarafından yutulmasını kapsayan bir süreçtir. Morfolojik değişimler, hücresel bütünlük ve canlılık için gerekli olan polipeptidlerin proteolitik yıkımı ile gerçekleşmektedir. Yıkım süreci spesifik sistein proteazlar grubu enzimler olan kaspazların aktive olması ile meydana gelmektedir. Apoptotik hücre ölüm mekanizmasında hücre içi bileşenlerin membran ile çevrilmiş apoptotik parçacıklar halinde çevre dokuya dağılması önemlidir. Bu nedenle nekrotik hücre ölüm mekanizması ile hücre içi bileşenlerin çevre dokuya dağılması sonucunda meydana gelen enflamasyon oluşmamaktadır. Günümüzde kanser tedavi stratejilerinin temel araştırma konularından biri; apoptoz mekanizması bozulmuş, sürekli proliferasyona uğrayan kanser hücrelerinin spesifik olarak yok edilmesini hedefleyen, apoptotik proteinlerin veya sinyal yolaklarının tetiklenmesini sağlayan tedavi stratejileri ile hücreyi apoptoza sürüklemektir.

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Cell, Volume 130, Issue 2, 223-233, 27 July 2007

Cellular senescence, a state of irreversible growth arrest, can be triggered by multiple mechanisms including telomere shortening, the epigenetic derepression of the INK4a/ARF locus, and DNA damage. Together these mechanisms limit excessive or aberrant cellular proliferation, and so the state of senescence protects against the development of cancer. Recent evidence suggests that cellular senescence also may be involved in aging.