Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality in the Western world with limited therapeutic options and dismal long-term survival. The neoplastic epithelium ...exists within a dense stroma, which is recognized as a critical mediator of disease progression through direct effects on cancer cells and indirect effects on the tumour immune microenvironment. The three dominant entities in the PDAC stroma are extracellular matrix (ECM), vasculature and cancer-associated fibroblasts (CAFs). The ECM can function as a barrier to effective drug delivery to PDAC cancer cells, and a multitude of strategies to target the ECM have been attempted in the past decade. The tumour vasculature is a complex system and, although multiple anti-angiogenesis agents have already failed late-stage clinical trials in PDAC, other vasculature-targeting approaches aimed at vessel normalization and tumour immunosensitization have shown promise in preclinical models. Lastly, PDAC CAFs participate in active cross-talk with cancer cells within the tumour microenvironment. The existence of intratumoural CAF heterogeneity represents a paradigm shift in PDAC CAF biology, with myofibroblastic and inflammatory CAF subtypes that likely make distinct contributions to PDAC progression. In this Review, we discuss our current understanding of the three principal constituents of PDAC stroma, their effect on the prevalent immune landscape and promising therapeutic targets within this compartment.
Vascular endothelial growth factor‐A (VEGF) is the predominant angiogenic factor that is expressed in solid tumors. Besides its critical function in mediating tumor angiogenesis, multiple studies ...have demonstrated that VEGF also contributes to tumor immunosuppression. VEGF interferes with immune cell trafficking indirectly by promoting a vascular immune barrier through VEGF receptor (VEGFR) activity on endothelial cells. However, VEGFRs are also expressed on multiple immune cell types, including T cells (effector T cells, Tregs) and myeloid cells (DCs, TAMs, MDSCs), where VEGF can have direct effects on immune cell phenotype and function. Thus, it is not surprising that strategies targeting VEGF/VEGFRs have shown efficacy in alleviating tumor‐associated immunosuppression and have been combined with immunotherapies, especially immune checkpoint blockade. In this review, we discuss the direct and indirect effects of VEGF on the immunosuppressive tumor microenvironment with particular focus on the direct regulation of immune cells through VEGFR2 activity. We also summarize preclinical and clinical observations of combining antiangiogenesis agents with immunotherapies for the treatment of solid tumors.
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Review on the function of vascular endothelial growth factor‐A (VEGF) in regulating immune cells in the tumor microenvironment and theuse of anti‐VEGF as cancer immunotherapy.
The exploration of new physical and chemical properties of materials and their innovative application in different fields are of great importance to advance analytical chemistry, material science, ...and other important fields. Herein, we, for the first time, discovered the photothermal effect of an iron oxide nanoparticles (NPs)-mediated TMB (3,3′,5,5′-tetramethylbenzidine)-H2O2 colorimetric system, and applied it toward the development of a new NP-mediated photothermal immunoassay platform for visual quantitative biomolecule detection using a thermometer as the signal reader. Using a sandwich-type proof-of-concept immunoassay, we found that the charge transfer complex of the iron oxide NPs-mediated one-electron oxidation product of TMB (oxidized TMB) exhibited not only color changes, but also a strong near-infrared (NIR) laser-driven photothermal effect. Hence, oxidized TMB was explored as a new sensitive photothermal probe to convert the immunoassay signal into heat through the near-infrared laser-driven photothermal effect, enabling simple photothermal immunoassay using a thermometer. Based on the new iron oxide NPs-mediated TMB-H2O2 photothermal immunoassay platform, prostate-specific antigen (PSA) as a model biomarker can be detected at a concentration as low as 1.0 ng·mL–1 in normal human serum. The discovered photothermal effect of the colorimetric system and the developed new photothermal immunoassay platform open up a new horizon for affordable detection of disease biomarkers and have great potential for other important material and biomedical applications of interest.
Highlights • The role of FN in tumor progression, metastasis, and chemoresistance of PDA is reviewed. • Regulation of FN signaling and expression in PDA is summarized to provide novel strategies to ...therapeutically target FN. • Current approaches to directly block FN signaling in PDA and its effect on tumor angiogenesis are reviewed.
There has been increasing interest in the detection of tumour exosomes in blood for cancer diagnostics. Most studies have focussed on miRNA and protein signatures that are surrogate markers for ...specific tumour types. Because tumour cells and tumour-derived exosomes display phosphatidylserine (PS) in their outer membrane leaflet, we developed a highly sensitive ELISA-based system that detects picogram amounts of exosomal phospholipid in plasma as a cancer biomarker.
This report describes the development of a highly specific and sensitive ELISA for the capture of PS-expressing tumour exosomes in the blood of tumour-bearing mice. To monitor the relationship between tumour burden and tumour exosome plasma concentrations, plasma from one transplantable breast cancer model (MDA-MB-231) and three genetic mouse models (MMTV-PyMT; breast and KIC and KPC; pancreatic) were screened for captured exosomal phospholipid.
We show that quantitative assessment of PS-expressing tumour exosomes detected very early-stage malignancies before clinical evidence of disease in all four model systems. Tumour exosome levels showed significant increases by day 7 after tumour implantation in the MDA-MB-231 model while palpable tumours appeared only after day 27. For the MMTV-PyMT and KIC models, tumour exosome levels increased significantly by day 49 (P⩽0.0002) and day 21 (P⩽0.001) while tumours developed only after days 60 and 40, respectively. For the KPC model, a significant increase in blood exosome levels was detected by day 70 (P=0.023) when only preinvasive lesions are microscopically detectable.
These data indicate that blood PS exosome levels is a specific indicator of cancer and suggest that blood PS is a biomarker for early-stage malignancies.
There is growing evidence that vascular endothelial growth factor-A (VEGF-A), a ligand of the receptor tyrosine kinases VEGFR1 and VEGFR2, promotes lymphangiogenesis. However, the underlying ...mechanisms by which VEGF-A induces the growth of lymphatic vessels remain poorly defined. Here we report that VEGFR2, not VEGFR1, is the primary receptor regulating VEGF-A-induced lymphangiogenesis. We show that specific inhibition of VEGF-A/VEGFR2 signaling with the fully human monoclonal antibody r84 significantly inhibits lymphangiogenesis in MDA-MB-231 tumors. In vitro experiments with primary human dermal lymphatic endothelial cells (LECs) demonstrate that blocking VEGF-A activation of VEGFR2, not VEGFR1, significantly inhibits VEGF-A-induced proliferation and migration of LECs. We show that VEGF-A stimulation of LECs leads to the phosphorylation of VEGFR2 (Tyr 951, 1054, 1059, 1175, and 1214) which subsequently triggers PKC dependent phosphorylation of ERK1/2 and PI3-K dependent phosphorylation of Akt. Additionally, we demonstrate that inhibitors that suppress the phosphorylation of ERK1/2 and Akt significantly block VEGF-A- induced proliferation and migration of LECs. Together, these results shed light on the mechanisms regulating VEGF-A-induced proliferation and migration of LECs, reveal that VEGFR2 is the primary signaling VEGF-A receptor on lymphatic endothelium, and suggest that therapeutic agents targeting the VEGF-A/VEGFR2 axis could be useful in blocking the pathological formation of lymphatic vessels.
Recent studies have identified a unique cancer-associated fibroblast (CAF) population termed antigen-presenting CAFs (apCAFs), characterized by the expression of major histocompatibility complex ...class II molecules, suggesting a function in regulating tumor immunity. Here, by integrating multiple single-cell RNA-sequencing studies and performing robust lineage-tracing assays, we find that apCAFs are derived from mesothelial cells. During pancreatic cancer progression, mesothelial cells form apCAFs by downregulating mesothelial features and gaining fibroblastic features, a process induced by interleukin-1 and transforming growth factor β. apCAFs directly ligate and induce naive CD4+ T cells into regulatory T cells (Tregs) in an antigen-specific manner. Moreover, treatment with an antibody targeting the mesothelial cell marker mesothelin can effectively inhibit mesothelial cell to apCAF transition and Treg formation induced by apCAFs. Taken together, our study elucidates how mesothelial cells may contribute to immune evasion in pancreatic cancer and provides insight on strategies to enhance cancer immune therapy.
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•Mesothelial cells are the cell of origin of apCAFs•apCAFs induce Treg formation in pancreatic cancer•Anti-mesothelin antibody can inhibit mesothelial cell-apCAF transition
Huang et al. discover that antigen-presenting cancer-associated fibroblasts (apCAFs) are derived from mesothelial cells in pancreatic cancer. apCAFs directly ligate and induce naive CD4+ T cells into regulatory T cells in an antigen-specific manner. They also demonstrate that mesothelial cell-apCAF transition can be inhibited by an anti-mesothelin monoclonal antibody.
To date, estrogen is the only known endogenous estrogen receptor (ER) ligand that promotes ER+ breast tumor growth. We report that the cholesterol metabolite 27-hydroxycholesterol (27HC) stimulates ...MCF-7 cell xenograft growth in mice. More importantly, in ER+ breast cancer patients, 27HC content in normal breast tissue is increased compared to that in cancer-free controls, and tumor 27HC content is further elevated. Increased tumor 27HC is correlated with diminished expression of CYP7B1, the 27HC metabolizing enzyme, and reduced expression of CYP7B1 in tumors is associated with poorer patient survival. Moreover, 27HC is produced by MCF-7 cells, and it stimulates cell-autonomous, ER-dependent, and GDNF-RET-dependent cell proliferation. Thus, 27HC is a locally modulated, nonaromatized ER ligand that promotes ER+ breast tumor growth.
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•27HC stimulates ER+ breast tumor growth in mice•27HC is increased in human ER+ breast tumors•Tumor CYP7B1 expression is negatively associated with prognosis•27HC causes cell-autonomous, ER-dependent, and RET-dependent proliferation
Resistance to endocrine-based therapies against estrogen-receptor (ER)-positive breast cancer is common. In this study, Shaul and colleagues show that the cholesterol metabolite 27-hydroxycholesterol (27HC) is a locally modulated, nonaromatized ER ligand that promotes ER+ breast tumor growth. 27HC content is abundant in ER+ tumors in women; this is related to diminished expression of the 27HC metabolizing enzyme CYP7B1, and reduced tumor CYP7B1 predicts poor survival. Strategies to lower 27HC may aid in the treatment of ER+ breast cancer.
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