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.
Highlights
Malignant melanoma (MM) accounts for 62% of all deaths caused by skin cancer [1]
This study investigated whether components of the renin-angiotensin system (RAS)—renin, pro-renin receptor (PRR), angiotensin-converting enzyme (ACE), ACE2, AT1 R, and AT2 R—were locally expressed by the cancer stem cells (CSCs) subpopulations that we have previously identified in
ACE was detected by western blotting (WB) in tissue samples, but not in head and neck metastatic malignant melanoma (HNmMM)-derived primary cell lines
Summary
New Zealand carry the most significant mortality burden [2,3], where the incidence of MM has been steadily increasing over the last 30 years [4] It is the third most common cancer in New Zealand men and women, with up to 35 new cases per 100,000 population annually [5]. CSCs are pluripotent stem cells with embryonic stem cell (ESC) properties including unlimited proliferative potential and the ability to undergo asymmetric division, giving rise to identical CSCs and differentiated cancer cells [10]. These differentiated cancer cells rapidly proliferate, making up the bulk of the tumor, and are susceptible to radiotherapy and chemotherapy which target rapidly dividing cells.
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