Post-translational modifications of the extracellular matrix are key events in cancer progression: Opportunities for biochemical marker development

Abstract

The aim of this review is to discuss the potential usefulness of a novel class of biochemical markers, designated neoepitopes. Neoepitopes are post-translational modifications (PTMs) of proteins and are derived by processes, such as protease cleavage, citrullination, nitrosylation, glycosylation and isomerization. Each PTM results from a specific local physiological or pathobiological process. Identification of each modification to a tissue-specific protein may reveal a unique disease-specific biochemical marker. During cancer metastasis, the host tissue is extensively degraded and replaced by cancer-associated extracellular matrix (ECM) proteins. Furthermore, severe cellular stress and inflammation, caused by cancer, results in generation of PTMs, which will be distributed throughout the ECM. This gives rise to release of protein-specific fragments to the circulation. Here we highlight the importance of remodeling of the ECM in cancer and the generation of PTMs, which may be cancer specific and reflect disease progression; thus having potential for biochemical marker development.

Extracellular Matrix Remodeling: The Common Denominator in Connective Tissue DiseasesPossibilities for Evaluation and Current Understanding of the Matrix as More Than a Passive Architecture, but a Key Player in Tissue Failure

“…Interestingly, both diseases involve aspects of inflammation and matrix assembly, destruction, and disorganization. 24,138,139 As illustrated in Figure 2, cancer cell metastasis results in extensive ECM remodeling (ECMR), resulting in the release of matrix components, including neoepitopes, into the circulation. ECM components and remodeling enzymes are known to be elevated in the circulation of cancer patients.…”

“…osteoarthritis affecting the articular cartilage (type II collagen and aggrecan) 56 . metabolic bone diseases (type I collagen) 138,[207][208][209][210] . sarcopenia (type VI collagen) [211][212][213] .…”

The Emerging Field of Diagnostics in Glycosylation Disorders

“…Although emerging rapidly, these methods still take considerable time and are expensive, therefore there is a need for more improved biochemical testing that can give comprehensive information on the effect on several glycoprotein or glycolipids, channelling the subsequent research into the definition of the exact step of the biosynthetic pathway of Biomarker discovery research is a growing field particularly in glycobiology, mostly due to the discovery that many cancers have altered glycosylation profiles [36,37]. However there is a lack of translation of markers into clinical laboratory tests.…”

Collagen degradation products measured in serum can separate ovarian and breast cancer patients from healthy controls: A preliminary study

“…Normal tissue homeostasis of the ECM is tightly controlled; here, old and damaged proteins of the ECM are degraded and replaced with new proteins. During cancer however this process is disturbed [5,6]; the protein composition changes, the ECM stiffens and increased levels of proteases are secreted. This leads to shift in the homeostasis of the ECM of which especially the interstitial fibrillar type I and III collagen, as well as the basement membrane protein type IV collagen play important roles [7,8].…”

“…protein fragments, are released into the circulation [5]. These protein fragments can, as they carry specific pathology dependent neo-epitopes, provide a unique tissue fingerprint of the combination of the involved proteases and the composition of the collagen.…”