Revisiting Circulating Extracellular Matrix Fragments as Disease Markers in Myelofibrosis and Related Neoplasms

Abstract

Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPNs) arise due to acquired somatic driver mutations in stem cells and develop over 10-30 years from the earliest cancer stages (essential thrombocythemia, polycythemia vera) towards the advanced myelofibrosis stage with bone marrow failure. The JAK2V617F mutation is the most prevalent driver mutation. Chronic inflammation is considered to be a major pathogenetic player, both as a trigger of MPN development and as a driver of disease progression. Chronic inflammation in MPNs is characterized by persistent connective tissue remodeling, which leads to organ dysfunction and ultimately, organ failure, due to excessive accumulation of extracellular matrix (ECM). Considering that MPNs are acquired clonal stem cell diseases developing in an inflammatory microenvironment in which the hematopoietic cell populations are progressively replaced by stromal proliferation-"a wound that never heals"-we herein aim to provide a comprehensive review of previous promising research in the field of circulating ECM fragments in the diagnosis, treatment and monitoring of MPNs. We address the rationales and highlight new perspectives for the use of circulating ECM protein fragments as biologically plausible, noninvasive disease markers in the management of MPNs.

Keywords: MPN; MPNs; circulating extracellular matrix (ECM) proteins; hyaluronan; laminin; myeloproliferative neoplasms; neoepitopes; procollagen type I C-terminal propeptide (PICP); protein fingerprints; serum procollagen III N-terminal propeptide (PIIINP); type IV collagen.

Figure 1

Circulating type III collagen fragments with specific neo-epitopes can be measured with the neo-epitope technology. Cells such as fibroblasts and reticular cells synthesize type III collagen. The type III pro-collagen is released into the extracellular space with subsequent proteolytic removal of the N-terminal propeptide and the C-terminal propeptide leading to collagen fibril formation and intrapeptide and interpeptide cross-linking with enzymes such as lysyl oxidase (LOX). Immune-mediated proteolysis with, e.g., metalloproteinases (MMPs) of the mature type III collagen results in the release of collagen fragments with specific neo-epitopes into the circulation. The neo-epitope technology is based on monoclonal antibodies, which enables the assessment of these specific neo-epitopes in serum or plasma. The biomarker PRO-C3 measures the C-terminal of the N-terminal propeptide, reflecting the true type III collagen formation, while PIIINP measures an internal epitope on the N-terminal propeptide. C3M measures MMP-degraded type III collagen reflecting fibrolysis, while CTX-3 measures cross-linked and MMP-degraded type III collagen.

Figure 2

Stroma of healthy bone marrow, myelofibrosis, healthy solid tissue and tumor fibrosis. The stroma of healthy bone marrow and healthy solid tissues are similar. These tissues are composed of fibroblasts, immune cells, fibers and amorphous ground substance, which consists mainly of proteoglycans, hyaluronan and collagens. The stroma in myelofibrosis and cancer are characterized by excessive inflammation and deposition of collagen fibers such as type I and type III collagen, as well as new blood vessel formation. In myelofibrosis, megakaryocytes are abundant in the bone marrow. Stroma generation in tumors and in bone marrow in myelofibrosis appear to follow an identical sequential pattern with oedema, angiogenesis and fibrosis.