Cancer Stem Cells in Head and Neck Metastatic Malignant Melanoma Express Components of the Renin-Angiotensin System

Abstract

Components of the renin-angiotensin system (RAS) are expressed by cancer stem cells (CSCs) in many cancer types. We here investigated expression of the RAS by the CSC subpopulations in human head and neck metastatic malignant melanoma (HNmMM) tissue samples and HNmMM-derived primary cell lines. Immunohistochemical staining demonstrated expression of pro-renin receptor (PRR), angiotensin-converting enzyme (ACE), and angiotensin II receptor 2 (AT2R) in all; renin in one; and ACE2 in none of the 20 HNmMM tissue samples. PRR was localized to cells within the tumor nests (TNs), while AT2R was expressed by cells within the TNs and the peritumoral stroma (PTS). ACE was localized to the endothelium of the tumor microvessels within the PTS. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) detected transcripts for PRR, ACE, ACE2, and AT1R, in all the five HNmMM tissue samples and four HNmMM-derived primary cell lines; renin in one tissue sample and one cell line, and AT2R in none of the five HNmMM tissue samples and cell lines. Western blotting showed variable expression of ACE, PRR, and AT2R, but not ACE2, in six HNmMM tissue samples and two HNmMM-derived primary cell lines. Immunofluorescence staining of two HNmMM tissue samples demonstrated expression of PRR and AT2R by the SOX2+ CSCs within the TNs and the OCT4+ CSCs within the PTS, with ACE localized to the endothelium of the tumor microvessels within the PTS.

Expression of Components of the Renin-Angiotensin System by Cancer Stem Cells in Renal Clear Cell Carcinoma

“…Our finding of the presence of components of the RAS by the CSCs within RCCC is consistent with findings of our previous studies of buccal mucosal [ 22 ], lip [ 21 ] and oral tongue [ 20 ] SCC, glioblastoma [ 19 ], primary HNcSCC [ 23 ], and mHNcSCC [ 24 ], metastatic MM to the braPLin [ 25 ] and regional lymph nodes [ 26 ], and metastatic colon adenocarcinoma to the liver [ 27 ]. We propose CSCs may be a potential novel therapeutic target by manipulation of the RAS [ 82 , 83 ].…”

“…The renin-angiotensin system (RAS) classically regulates blood pressure and body fluid homeostasis [ 18 ]. We have demonstrated the expression of components of the RAS by CSCs in many cancer types including glioblastoma [ 19 ], oral cavity squamous cell carcinoma of different subsites [ 20 , 21 , 22 ], primary head and neck cutaneous squamous cell carcinoma (HNcSCC) [ 23 ] and metastatic HNcSCC (mHNcSCC) [ 24 ], metastatic malignant melanoma (MM) to the brain [ 25 ] and regional lymph nodes [ 26 ], and metastatic colon adenocarcinoma [ 27 ]. We have also demonstrated expression of cathepsins B, D and G which constitute bypass loops of the RAS [ 28 ], in a number of cancer types [ 29 , 30 , 31 , 32 ].…”

Telmisartan/hydrochlorothiazide-induced nevus-associated cutaneous melanoma: first report in the medical literature

“…The presence of angiotensin receptors in metastatic melanoma tissue (a third major reference point for the relationship between sartan intake and melanoma development) [16], and the experimentally potentiated carcinogenic effect of losartan…”

“…This is further supported by the de novo development of a nevus 2 years after the introduction of therapy with telmisartan and hydrochlorothiazide, and its relatively rapid transition to cutaneous melanoma -a fact that was apparent from both the clinical and dermatoscopic images (Figure 1(a,b)) and subsequently confirmed histologically. Given the findings of investigative studies to date [16][17][18], we believe there is a possible pathogenetic explanation for the development of melanoma, or the rapid transition of nevus to melanoma, related to the administration of telmisartan and hydrochlorothiazide [7,8,17]. According to the literature, nevus-associated melanomas represent about 30% of registered melanomas worldwide [19,20].…”

Cancer Stem Cells in Metastatic Head and Neck Cutaneous Squamous Cell Carcinoma Express Components of the Renin-Angiotensin System

“…We have recently demonstrated the expression of components of the RAS: PRR, ACE, AT 1 R, and AT 2 R by the CSCs in different cancer types, including OCSCC of different subsites [ 47 , 48 ], glioblastoma [ 8 ], metastatic malignant melanoma to the brain [ 18 ] and regional nodes [ 49 ], metastatic colon adenocarcinoma [ 50 ], and primary HNcSCC [ 51 ]. This study aimed to investigate the expression of components of the RAS: angiotensinogen, renin, PRR, ACE, ACE2, AT 1 R, and AT 2 R, in relation to the CSC subpopulations we have identified in mHNcSCC [ 20 ].…”