Formalin-fixed
paraffin-embedded (FFPE) tissue represents the primary
source of clinical tissue and is routinely used in MALDI-MSI studies.
However, it is not particularly suitable for lipidomics imaging given
that many species are depleted during tissue processing. Irrespective,
a number of solvent-resistant lipids remain, but their extraction
may be hindered by the cross-link between proteins. Therefore, an
antigen retrieval step could enable the extraction of a greater number
of lipids and may provide information that is complementary to that
which can be obtained from other biomolecules, such as proteins. In
this short communication, we aim to address the effect of performing
antigen retrieval prior to MALDI-MSI of lipids in FFPE tissue. As
a result, an increased number of lipid signals could be detected and
may have derived from lipid species that are known to be implicated
in the lipid–protein cross-linking that is formed as a result
of formalin fixation. Human renal cancer tissue was used as a proof
of concept to determine whether using these detected lipid signals
were also able to highlight the histopathological regions that were
present. These preliminary findings may highlight the potential to
enhance the clinical relevance of the lipidomic information obtained
from FFPE tissue.
Transglutaminase-2 (TG2) is the most highly and ubiquitously expressed member of the transglutaminase enzyme family and is primarily involved in protein cross-linking. TG2 has been implicated in the development and progression of numerous cancers, with a direct role in multiple cellular processes and pathways linked to apoptosis, chemoresistance, epithelial-mesenchymal transition, and stem cell phenotype. The tumour microenvironment (TME) is critical in the formation, progression, and eventual metastasis of cancer, and increasing evidence points to a role for TG2 in matrix remodelling, modulation of biomechanical properties, cell adhesion, motility, and invasion. There is growing interest in targeting the TME therapeutically in response to advances in the understanding of its critical role in disease progression, and a number of approaches targeting biophysical properties and biomechanical signalling are beginning to show clinical promise. In this review we aim to highlight the wide array of processes in which TG2 influences the TME, focussing on its potential role in the dynamic tissue remodelling and biomechanical events increasingly linked to invasive and aggressive behaviour. Drug development efforts have yielded a range of TG2 inhibitors, and ongoing clinical trials may inform strategies for targeting the biomolecular and biomechanical function of TG2 in the TME.
Introduction: Diabetic nephropathy (DN) and hypertensive nephrosclerosis (HN) represent the most common causes of chronic kidney disease (CKD) and many patients progress to end-stage renal disease. Patients are treated primarily through the management of cardiovascular risk factors and hypertension; however patients with HN have a more favorable outcome. A noninvasive clinical approach to separate these two entities, especially in hypertensive patients who also have diabetes, would allow for targeted treatment and more appropriate resource allocation to those patients at the highest risk of CKD progression. Methods: In this preliminary study, high-spatial-resolution matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) was integrated with high-mass accuracy MALDI-FTICR-MS and nLC-ESI-MS/MS analysis in order to detect tissue proteins within kidney biopsies to discriminate cases of DN (n = 9) from cases of HN (n = 9). Results: Differences in the tryptic peptide profiles of the 2 groups could clearly be detected, with these becoming even more evident in the more severe histological classes, even if this was not evident with routine histology. In particular, 4 putative proteins were detected and had a higher signal intensity within regions of DN tissue with extensive sclerosis or fibrosis. Among these, 2 proteins (PGRMC1 and CO3) had a signal intensity that increased at the latter stages of the disease and may be associated with progression. Discussion/Conclusion: This preliminary study represents a valuable starting point for a future study employing a larger cohort of patients to develop sensitive and specific protein biomarkers that could reliably differentiate between diabetic and hypertensive causes of CKD to allow for improved diagnosis, fewer biopsy procedures, and refined treatment approaches for clinicians.
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