Cancer vaccines: Building a bridge over troubled waters

Abstract Tumors are comprised of both cancer cells and surrounding stromal components. As an essential part of the tumor microenvironment, the tumor stroma is highly dynamic, heterogeneous and commonly tumor-type specific, and it mainly includes noncellular compositions such as the extracellular matrix and the unique cancer-associated vascular system as well as a wide variety of cellular components including activated cancer-associated fibroblasts, mesenchymal stromal cells, pericytes. All these elements operate with each other in a coordinated fashion and collectively promote cancer initiation, progression, metastasis and therapeutic resistance. Over the past few decades, numerous studies have been conducted to study the interaction and crosstalk between stromal components and neoplastic cells. Meanwhile, we have also witnessed an exponential increase in the investigation and recognition of the critical roles of tumor stroma in solid tumors. A series of clinical trials targeting the tumor stroma have been launched continually. In this review, we introduce and discuss current advances in the understanding of various stromal elements and their roles in cancers. We also elaborate on potential novel approaches for tumor-stroma-based therapeutic targeting, with the aim to promote the leap from bench to bedside. 

/pdf/targeting-the-tumor-stroma-for-cancer-therapy-sjndz6yj.pdf

Targeting the tumor stroma for cancer therapy

Fibroblast heterogeneity in solid tumors: from single cell analysis to whole-body imaging.

Cancer-associated fibroblasts: Vital suppressors of the immune response in the tumor microenvironment.

Simple Summary Cell surface proteases (so-called ectoproteases) are associated with cancer, and their targeting may confer valuable options for the improvement of cancer treatment outcome. Over the past 20 years, the permanent development of a multitude of inhibitors against several ectoproteases (including DPP4, FAP, APN, ADAM17, MMP2, and MMP9) has made it into clinical evaluation in haematological and solid tumours. Among them, a few show some efficacy, albeit limited, to cure cancer in the near future. This Review summarizes the efforts thus far undertaken in the development of ectoprotease inhibitors and highlights new directions for targeting ectoproteases as an additional weapon in the fight against cancer. Abstract Cell surface proteases (also known as ectoproteases) are transmembrane and membrane-bound enzymes involved in various physiological and pathological processes. Several members, most notably dipeptidyl peptidase 4 (DPP4/CD26) and its related family member fibroblast activation protein (FAP), aminopeptidase N (APN/CD13), a disintegrin and metalloprotease 17 (ADAM17/TACE), and matrix metalloproteinases (MMPs) MMP2 and MMP9, are often overexpressed in cancers and have been associated with tumour dysfunction. With multifaceted actions, these ectoproteases have been validated as therapeutic targets for cancer. Numerous inhibitors have been developed to target these enzymes, attempting to control their enzymatic activity. Even though clinical trials with these compounds did not show the expected results in most cases, the field of ectoprotease inhibitors is growing. This review summarizes the current knowledge on this subject and highlights the recent development of more effective and selective drugs targeting ectoproteases among which small molecular weight inhibitors, peptide conjugates, prodrugs, or monoclonal antibodies (mAbs) and derivatives. These promising avenues have the potential to deliver novel therapeutic strategies in the treatment of cancers.

/pdf/validating-cell-surface-proteases-as-drug-targets-for-cancer-3s928hso.pdf

Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go?

Fibroblast activation protein-α (FAP) is a type II integral serine protease that is specifically expressed by activated fibroblasts. Cancer-associated fibroblasts (CAFs) in the tumor stroma have abundant and stable expression of FAP, which plays an important role in promoting tumor growth, invasion, metastasis, and immunosuppression. For example, in women with a high incidence of breast cancer, CAFs account for 50–70% of the cells in the tumor’s microenvironment. CAF overexpression of FAP promotes tumor development and metastasis by influencing extracellular matrix remodeling, intracellular signaling, angiogenesis, epithelial-to-mesenchymal transition, and immunosuppression. This review covers the basic biological characteristics of FAP and its applications in the diagnosis and treatment of various cancers. Furthermore, we review the emerging basic and clinical research data regarding the use of nanomaterials that target FAP.

/pdf/fibroblast-activation-protein-a-as-a-target-in-the-bench-to-1ee34rmt2t.pdf

Yiyou Chen

Papers

Fibroblast Activation Protein-α as a Target in the Bench-to-Bedside Diagnosis and Treatment of Tumors: A Narrative Review.