Effects of CD73 on human colorectal cancer cell growth in vivo and in vitro

Wu, Ruimin; Chen, Yijia; Li, Fuyan; Li, Wei; Zhou, Hong; Yang, Yi; Pei, Zhijun

doi:10.3892/or.2015.4512

Cited by 39 publications

(45 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In line with this, the CMS2 group predicts tumors that are more responsive to anti-EGFR and anti-HER2 therapy (235). Also consistent is that CD73 promotes CRC cell proliferation and tumor growth through β-catenin (WNT)/cyclin D1 signaling (236) and CMS2 tumors are characterized by WNT and MYC signaling (233). KRAS mutations/alterations are likely also linked to CD73 expression in CRC; discussed previously in the section on PDAC (207).…”

Section: Colorectal Cancermentioning

confidence: 56%

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

et al. 2020

View full text Add to dashboard Cite

CD73, a cell surface 5 ′ nucleotidase that generates adenosine, has emerged as an attractive therapeutic target for reprogramming cancer cells and the tumor microenvironment to dampen antitumor immune cell evasion. Decades of studies have paved the way for these findings, starting with the discovery of adenosine signaling, particularly adenosine A2A receptor (A2AR) signaling, as a potent suppressor of tissue-devastating immune cell responses, and evolving with studies focusing on CD73 in breast cancer, melanoma, and non-small cell lung cancer. Gastrointestinal (GI) cancers are a major cause of cancer-related deaths. Evidence is mounting that shows promise for improving patient outcomes through incorporation of immunomodulatory strategies as single agents or in combination with current treatment options. Recently, several immune checkpoint inhibitors received FDA approval for use in GI cancers; however, clinical benefit is limited. Investigating molecular mechanisms promoting immunosuppression, such as CD73, in GI cancers can aid in current efforts to extend the efficacy of immunotherapy to more patients. In this review, we discuss current clinical and basic research studies on CD73 in GI cancers, including gastric, liver, pancreatic, and colorectal cancer, with special focus on the potential of CD73 as an immunotherapy target in these cancers. We also present a summary of current clinical studies targeting CD73 and/or A2AR and combination of these therapies with immune checkpoint inhibitors.

show abstract

Section: Colorectal Cancermentioning

confidence: 56%

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Elevated tumor CD73 levels are associated with poor clinical outcomes in several tumor types 7,9,[26][27][28] . Nevertheless, most of the correlative studies were based on CD73 expression in unfractionated tumor tissues.…”

Section: Resultsmentioning

confidence: 99%

“…Clinical association between elevated CD73 expression and poor prognosis has been well documented in many tumor types 7,9,[26][27][28]49,56 . The contribution of CD73 activity in Tregs and vasculature to this overall CD73-mediated immunosuppression has been well demonstrated 24,[45][46][47] .…”

Section: Discussionmentioning

confidence: 99%

CD73 on cancer-associated fibroblasts enhanced by the A2B-mediated feedforward circuit enforces an immune checkpoint

et al. 2020

View full text Add to dashboard Cite

CD73, an ecto-5′-nucleotidase (NT5E), serves as an immune checkpoint by generating adenosine (ADO), which suppresses immune activation through the A 2A receptor. Elevated CD73 levels in tumor tissues correlate with poor clinical outcomes. However, the crucial source of CD73 activity within the tumor microenvironment remains unspecified. Here, we demonstrate that cancer-associated fibroblasts (CAFs) constitute the prominent CD73 hi population in human colorectal cancers (CRCs) and two CD73 − murine tumor models, including a modified CRC. Clinically, high CAF abundancy in CRC tissues correlates strongly with elevated CD73 activity and poor prognosis. Mechanistically, CAF-CD73 expression is enhanced via an ADO-A 2B receptor-mediated feedforward circuit triggered by tumor cell death, which enforces the CD73-checkpoint. Simultaneous inhibition of A 2A and A 2B pathways with CD73-neutralization synergistically enhances antitumor immunity in CAF-rich tumors. Therefore, the strategic and effective targeting of both the A 2B-mediated ADO-CAF-CD73 feedforward circuit and A 2A-mediated immune suppression is crucial for improving therapeutic outcomes.

show abstract

“…The effectiveness of reaction quenching using 1% formic acid (final 0.05% after dilution with 20 volumes of water) was confirmed by monitoring the amount of [ 15 Results showed excellent agreement with those obtained using a single-substrate assay (Suppl. Fig.…”

Section: Cd73 Assay Development and Optimizationmentioning

confidence: 58%

“…Testing compounds were first prepared by serial threefold dilution with DMSO, then further diluted to an appropriate concentration with cell growth media. Diluted compounds (33 µL) were added to exponentially growing cells (to yield 100 µL total volume) and were pre-incubated with the cells for 15-30 min prior to the addition of reaction substrate [ 15…”

Section: Cellular Cd73 Assaymentioning

confidence: 99%

A Robust Multiplex Mass Spectrometric Assay for Screening Small-Molecule Inhibitors of CD73 with Diverse Inhibition Modalities

McManus

Gavigan

et al. 2018

SLAS Discovery

View full text Add to dashboard Cite

CD73/Ecto-5'-nucleotidase is a membrane-tethered ecto-enzyme that works in tandem with CD39 to convert extracellular adenosine triphosphate (ATP) into adenosine. CD73 is highly expressed on various types of cancer cells and on infiltrating suppressive immune cells, leading to an elevated concentration of adenosine in the tumor microenvironment, which elicits a strong immunosuppressive effect. In preclinical studies, targeting CD73 with anti-CD73 antibody results in favorable antitumor effects. Despite initial studies using antibodies, inhibition of CD73 catalytic activity using small-molecule inhibitors may be more effective in lowering extracellular adenosine due to better tumor penetration and distribution. To screen small-molecule libraries, we explored multiple approaches, including colorimetric and fluorescent biochemical assays, and due to some limitations with these assays, we developed a mass spectrometry (MS)-based assay. Only the MS-based assay offers the sensitivity and dynamic range required for screening small-molecule libraries at a substrate concentration close to the K value of substrate and for evaluating the mode of binding of screening hits. To achieve a throughput suitable for high-throughput screening (HTS), we developed a RapidFire-tandem mass spectrometry (RF-MS/MS)-based multiplex assay. This assay allowed a large diverse compound library to be screened at a speed of 1536 reactions per 40-50 min.

show abstract

Effects of CD73 on human colorectal cancer cell growth in vivo and in vitro

Cited by 39 publications

References 38 publications

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

CD73 on cancer-associated fibroblasts enhanced by the A2B-mediated feedforward circuit enforces an immune checkpoint

A Robust Multiplex Mass Spectrometric Assay for Screening Small-Molecule Inhibitors of CD73 with Diverse Inhibition Modalities

Contact Info

Product

Resources

About