The Tumor Proteolytic Landscape: A Challenging Frontier in Cancer Diagnosis and Therapy

Abstract

In recent decades, dysregulation of proteases and atypical proteolysis have become increasingly recognized as important hallmarks of cancer, driving community-wide efforts to explore the proteolytic landscape of oncologic disease. With more than 100 proteases currently associated with different aspects of cancer development and progression, there is a clear impetus to harness their potential in the context of oncology. Advances in the protease field have yielded technologies enabling sensitive protease detection in various settings, paving the way towards diagnostic profiling of disease-related protease activity patterns. Methods including activity-based probes and substrates, antibodies, and various nanosystems that generate reporter signals, i.e., for PET or MRI, after interaction with the target protease have shown potential for clinical translation. Nevertheless, these technologies are costly, not easily multiplexed, and require advanced imaging technologies. While the current clinical applications of protease-responsive technologies in oncologic settings are still limited, emerging technologies and protease sensors are poised to enable comprehensive exploration of the tumor proteolytic landscape as a diagnostic and therapeutic frontier. This review aims to give an overview of the most relevant classes of proteases as indicators for tumor diagnosis, current approaches to detect and monitor their activity in vivo, and associated therapeutic applications.

Biological Evaluation, Molecular Docking Analyses, and ADME Profiling of Certain New Quinazolinones as Anti-colorectal Agents

“…Furthermore, high levels of other proteases, such as neutrophil elastase 13 and trypsin, 14 stimulate degradation of the extracellular matrix and promote evasion of immune system, invasion, metastasis, and resistance to apoptotic signals. 15 …”

Large‐Scale Dried Reagent Reconstitution and Diffusion Control Using Microfluidic Self‐Coalescence Modules

“…[32] Proteases are currently intensively studied in the context of cancer diagnosis, imaging, and therapy but such enzymes are scarce, costly, and may lack specificity. [33,34] By pairing proteases with selected combinations of peptides within diffusional control, a large combination of enzyme-substrates may be screened efficiently.…”

Proteases Regulate Cancer Stem Cell Properties and Remodel Their Microenvironment

“…[43][44][45] By taking part in various proteolytic cascades and networks, proteases are involved in several processes of tumor development and progression, 39,[46][47][48][49] as summarized in Table 1. The primary function of proteases derived from either cancer or non-cancerous cells in the tumor microenvironment (TME) 38,39,60 is not only ECM degradation, as originally anticipated, but also the modulation of other pericellular events, in particular the activity and bioavailability of growth factors, cytokines, cell surface receptors, and adhesion molecules, as well as the modulation of intracellular signaling pathways. 39,49,50 Some proteases or their domains also possess non-enzymatic functions, 50 such as the inactive proform of cathepsin X 74 and several MMPs whose hemopexin domain is involved in protein-protein interactions.…”

“…Furthermore, protease regulation is enhanced by the presence of selective endogenous protease inhibitors. 19,[35][36][37] Dysregulated proteolysis underlies numerous pathologies, including cancer, 38,39 where proteases are most commonly upregulated and act as protumorigenic factors. [40][41][42] However, some proteases are also involved in tumor suppression and are downregulated in cancer.…”

“…[40][41][42] However, some proteases are also involved in tumor suppression and are downregulated in cancer. [43][44][45] By taking part in various proteolytic cascades and networks, proteases are involved in several processes of tumor development and progression, 39,[46][47][48][49] as summarized in Table 1. The primary function of proteases derived from either cancer or non-cancerous cells in the tumor microenvironment (TME) 38,39,60 is not only ECM degradation, as originally anticipated, but also the modulation of other pericellular events, in particular the activity and bioavailability of growth factors, cytokines, cell surface receptors, and adhesion molecules, as well as the modulation of intracellular signaling pathways.…”