Cancer stem cells in liver metastasis from colon adenocarcinoma express components of the renin-angiotensin system

Abstract

Aim: We have recently identified a cancer stem cell (CSC) subpopulations within the tumor nests (TNs) and another within the peritumoral stroma (PTS) in liver metastasis from colon adenocarcinoma (LMCA). This study investigated the expression of components of the renin-angiotensin (RAS): pro-renin receptor (PRR), angiotensin converting enzyme (ACE), and angiotensin II receptor 1 (ATIIR1) and angiotensin II receptor 2 (ATIIR2) in LMCA. Methods: 3,3-Diaminobenzidine (DAB) immunohistochemical (IHC) staining was performed on 16 LMCA samples for PRR, ACE, ATIIR1 and ATIIR2. Immunofluorescence (IF) IHC staining was performed to investigate co-expression of these components of the RAS with SOX2 or OCT4. NanoString analysis (n = 6) and Western blotting (WB, n = 3) were performed on snap-frozen LMCA samples to confirm mRNA and protein expression, respectively. Results: DAB IHC staining showed the expression of PRR, ACE, ATIIR1 and ATIIR2 within all LMCA samples. NanoString analysis and WB confirmed gene and protein expression of these components of the RAS. IF IHC staining demonstrated expression of PRR, ATIIR1 and ATIIR2 by the SOX2 + CSCs within the TNs and the OCT4 + CSCs within the PTS. ACE was expressed on the endothelium of the microvessels within the PTS. Conclusion: These finding suggests the CSCs within LMCA maybe a novel therapeutic target by manipulation of the RAS.

Cancer Stem Cells in Head and Neck Cutaneous Squamous Cell Carcinoma Express Cathepsins

“…CSCs have been identified in many cancer types, including OCSCC of different subsites, 9 – 11 glioblastoma, 12 renal clear cell carcinoma, 13 primary 14 and metastatic 15 colon adenocarcinoma, and metastatic malignant melanoma. 16 , 17 We have recently reported the presence of 4 CSC subpopulations within human MDHNcSCC: an OCT4 + /NANOG + /SOX2 + /KLF4 + /c-MYC + subpopulation within the TNs, the PTS, the endothelium of the microvessels within the PTS, and an OCT4 + /NANOG − /SOX2 + /KLF4 + /c-MYC + subpopulation solely within the PTS.…”

“…Recent reports demonstrate the expression of RAS on CSC components in many cancer types, including glioblastoma, 20 oral tongue 21 and buccal mucosal 22 SCC, metastatic colon adenocarcinoma, 15 and metastatic malignant melanoma. 24 Recent literature suggests a key role for the RAS in tumorigenesis, 29 – 31 with many studies demonstrating a reduced recurrence and overall increased survival of cancer patients who are administered RAS inhibitors.…”

“…CSCs have been identified in many cancer types, including oral cavity SCC (OCSCC) of different subsites, 9 – 11 glioblastoma, 12 renal clear cell carcinoma, 13 primary 14 and metastatic 15 colon adenocarcinoma, and metastatic malignant melanoma. 16 , 17 …”

“…Expression of components of the renin–angiotensin system (RAS) by CSCs has been demonstrated in different cancer types, including glioblastoma, 20 OCSCC, 21 – 23 metastatic colon adenocarcinoma, 15 and metastatic malignant melanoma, 24 suggesting the potential of targeting CSCs by modulating the RAS. 25 , 26 …”

Therapeutic Targeting of Cancer Stem Cells in Human Glioblastoma by Manipulating the Renin-angiotensin System

“…The RAS has been implicated in the hallmarks of cancer (George, Thomas et al 2010, Wegman-Ostrosky, Soto-Reyes et al 2015. We have demonstrated the expression of components of the RAS: PRR, ACE, ATIIR1 and ATIIR2 by CSCs in different cancer types including head and neck cutaneous squamous cell carcinoma (SCC) (Nallaiah, Lee et al 2019), oral cavity SCC (OCSCC) affecting the lip (Ram, Brasch et al 2017), buccal mucosa (Featherston, Yu et al 2016) and oral tongue , liver metastases from colon adenocarcinoma (Narayanan, Wickremesekera et al 2019) and metastatic melanoma to the brain (Wickremesekera, Brasch et al 2019). More importantly, components of the RAS: PRR, ATIIR1 and ATIIR2 have been shown to be expressed by the CSCs in GB with ACE and also PRR, ATIIR1 and ATIIR2 localizing to the endothelium of the microvessels (Figure 2).…”