Angiotensin-converting enzyme and the tumor microenvironment: mechanisms beyond angiogenesis

Okwan-Duodu, Derick; Landry, Jerome C.; Shen, Xiao Z.; Díaz, Roberto

doi:10.1152/ajpregu.00544.2012

Cited by 44 publications

(29 citation statements)

References 158 publications

(175 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…While ACEis act inhibiting the conversion of angiotensin I to angiotensin II, ARBs act on the receptors of this hormone. The protective effect of ACEis has been demonstrated in animal models of solid cancers [40,41], but certain authors have also found that the chronic treatment with ACEis might produce the accumulation of some peptides with protumor effect, such as bradykinin, substance P, and Nacetyl-seryl-aspartyl-lysyl-proline [42]. ARBs, in turn, selectively block the angiotensin II type 1 receptors, responsible for vasoconstriction, cell growth, and sympathetic activation and in this way exerts their potential antineoplastic effect, maintaining the beneficial effects of angiotensin II type 2-receptor stimulation (vasodilatory and antiproliferative action mediated via the kinin system) [21,37].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Relationship between drugs affecting the renin-angiotensin system and colorectal cancer: The MCC-Spain study

Dierssen-Sotos

Gómez‐Acebo

Palazuelos

et al. 2017

Preventive Medicine

View full text Add to dashboard Cite

The potential protective effect of Renin-angiotensin system (RAS) inhibitors is a subject of increasing interest due to their possible role as chemopreventive agents against colorectal cancer (CRC). To evaluate this association, we conducted a case-control study with 2,165 cases of colorectal cancer, diagnosed between 2007 and 2012, and 3,912 population controls frequency matched (by age, sex and region) from the Spanish multicenter case-control study MCC-Spain. We found a significant protective effect of the Angiotensin-converting enzyme Inhibitors (ACEIs) against CRC, limited to the under-65 years group (OR=0.65 95%CI (0.48-0.89)) and to a lesser degree to men (OR=0.81 95%CI (0.66-0.99). In contrast, the angiotensin receptor blockers (ARBs) did not show a significant effect. Regarding the duration of use, a greater protection was observed in men as the length of consumption increases. In contrast, in the under-65 stratum, the strongest association was found in short-term treatments. Finally, by analyzing ACEIs effect by colon subsite, we found no differences, except for under 65 years old, where the maximum protection was seen in the proximal intestine, descending in the distal and rectum (without statistical significance). In conclusion, our study shows a protective effect on CRC of the ACEis limited to males and people under 65 years old, which increases in proximal colon in the latter. If confirmed, these results may suggest a novel approach to proximal CRC prevention, given the shortcomings of colonoscopy screening in this location.

show abstract

Section: Accepted Manuscriptmentioning

confidence: 99%

Relationship between drugs affecting the renin-angiotensin system and colorectal cancer: The MCC-Spain study

Dierssen-Sotos

Gómez‐Acebo

Palazuelos

et al. 2017

Preventive Medicine

View full text Add to dashboard Cite

show abstract

“…However, the reality is much more challenging to monitor because of the large degree of fluctuation in abundance and localization of these tumor-secreted proteins, especially in the early stage of tumor development and/or metastasis (5, 6). As such, it seems feasible that we might take advantage of the fact that secreted proteases/peptidases in the tumor microenvironment generate proteolytic products, also referred to as “circulating peptides”, and these are continuously released into interstitial fluid, lymph, eventually making their way into the bloodstream (7). Consequently, blood samples can provide ample information about the body, “coded” in the patterns and quantity of these peptides (8).…”

Section: Introductionmentioning

confidence: 99%

Circulating Proteolytic Products of Carboxypeptidase N for Early Detection of Breast Cancer

Chen

et al. 2014

Clinical Chemistry

View full text Add to dashboard Cite

Background Carboxypeptidase N (CPN) plays an important role in regulating vasoactive peptide hormones, growth factors, and cytokines by specifically cleaving their C-terminal basic residues. Herein we demonstrated that the circulating peptides specifically cleaved by CPN in the tumor microenvironment can indeed be stage-specific indicators of breast cancer. Methods The activity of CPN was evaluated using an ex-vivo peptide cleavage assay, in which synthesized C3f peptide (His6-C3f_S1304-R1320-His6) is incubated in interstitial fluids of breast tumor and adjacent normal breast tissues in mice with orthotopic implantation of the human cell line MDA-MB-231. Fragment profiling, by an approach combining nanopore fractionation and mass spectrometry, revealed the nature and extent of cleavage by CPN. These results correlated with the level of CPN-catalyzed peptides in blood specimens taken from the tumor-bearing mice, healthy women and breast cancer patients. CPN expression in the same set of samples was further examined by immunohistochemistry and immunoblotting. Results We showed that generation of C3f_R1310-L1319 specifically correlated with the CPN expression level. In both the mouse and clinical patient samples, the amount of CPN was clearly increased in tumor tissues compared to that seen in normal breast tissue, while its counterpart in blood remained constant. The amount of 6 CPN-catalyzed peptides predominantly increased in sera taken from the mice (n=8) at 2 weeks after orthotropic implantation. Six homologous peptides displayed the significantly higher expression in the patients’ plasma as early as the first pathologic stage of breast cancer. Conclusions The amount of circulating CPN-catalyzed peptides reported here reflects the extent of this enzyme’s activity in tumors, and our results clearly indicate their strong potential as biomarkers for non-invasive and early diagnosis of breast cancer.

show abstract

“…Support for this hypothesis also comes from pre-clinical studies demonstrating that oxidative damage, from both cardiac etiologies [30] and radiation therapy [31], dysregulates the ACE/angiotensin pathway, leading to elevated levels of TGFB and VEGF, molecules essential to the pathogenesis of fibrosis and poor organ function; ABT is able to modulate these pathways and lead to decrease late side effects in vivo [32]. Overall, these pre-clinical and clinical studies provide multiple levels of support to our findings that ABT is associated with lower risk of SRN after intracranial SRS.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin receptor blockade: a novel approach for symptomatic radiation necrosis after stereotactic radiosurgery

et al. 2017

Self Cite

View full text Add to dashboard Cite

Preclinical evidence suggests angiotensin blockade therapy (ABT) decreases late radiation toxicities. This study aims to investigate the association between ABT and symptomatic radiation necrosis (SRN) following stereotactic radiosurgery (SRS). Resected brain metastases (rBM) and arteriovenous malformation (AVM) patients treated with SRS from 2002 to 2015 were identified. Patients in the ABT cohort were on therapy during SRS and at 1-month follow up. Kaplan Meier method and cumulative incidence model were used to analyze overall survival (OS) and intracranial outcomes. 228 consecutive patients were treated with SRS: 111 with rBM and 117 with AVM. Overall, 51 (22.4%) patients were in the ABT group: 32 (28.8%) in the rBM and 19 (16.2%) in AVM cohorts. Baseline characteristics were similar, except for higher Graded Prognostic Analysis (3–4) in the rBM (ABT: 25.0% vs. non-ABT: 49.0%, p = 0.033) and median age in the AVM (ABT: 51.4 vs. non-ABT: 35.4, p < 0.001) cohorts. In both populations, OS and intracranial efficacy (rBM—local control; AVM—obliteration rates) were statistically similar between the cohorts. ABT was associated with lower 1-year SRN rates in both populations: rBM, 3.1 versus 25.3% (p = 0.003); AVM, 6.7 vs. 14.6% (p = 0.063). On multivariate analysis, ABT was a significant predictive factor for rBM (HR: 0.17; 95% CI 0.03–0.88, p = 0.035), but did not reach statistical significance for AVM (HR: 0.36; 95% CI 0.09–1.52, p = 0.165). ABT use appears to be associated with a reduced risk of SRN following SRS, without detriment to OS or intracranial efficacy. A prospective trial to validate these findings is warranted.

show abstract

Angiotensin-converting enzyme and the tumor microenvironment: mechanisms beyond angiogenesis

Cited by 44 publications

References 158 publications

Relationship between drugs affecting the renin-angiotensin system and colorectal cancer: The MCC-Spain study

Relationship between drugs affecting the renin-angiotensin system and colorectal cancer: The MCC-Spain study

Circulating Proteolytic Products of Carboxypeptidase N for Early Detection of Breast Cancer

Angiotensin receptor blockade: a novel approach for symptomatic radiation necrosis after stereotactic radiosurgery

Contact Info

Product

Resources

About