Cancer Stem Cells and the Renin-Angiotensin System in the Tumor Microenvironment of Melanoma: Implications on Current Therapies

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2025 Feb 13

PMID 39941158

Authors

Ethan J Kilmister

Swee T Tan

Affiliations

Soon will be listed here.

Abstract

Multiple signaling pathways are dysregulated in melanoma, notably the Ras/RAF/MAPK/ERK and PI3K/AKT/mTOR pathways, which can be targeted therapeutically. The high immunogenicity of melanoma has been exploited using checkpoint inhibitors. Whilst targeted therapies and immune checkpoint inhibitors have improved the survival of patients with advanced melanoma, treatment resistance, their side effect profiles, and the prohibitive cost remain a challenge, and the survival outcomes remain suboptimal. Treatment resistance has been attributed to the presence of cancer stem cells (CSCs), a small subpopulation of pluripotent, highly tumorigenic cells proposed to drive cancer progression, recurrence, metastasis, and treatment resistance. CSCs reside within the tumor microenvironment (TME) regulated by the immune system, and the paracrine renin-angiotensin system, which is expressed in many cancer types, including melanoma. This narrative review discusses the role of CSCs and the paracrine renin-angiotensin system in the melanoma TME, and its implications on the current treatment of advanced melanoma with targeted therapy and immune checkpoint blockers. It also highlights the regulation of the Ras/RAF/MAPK/ERK and PI3K/AKT/mTOR pathways by the renin-angiotensin system via pro-renin receptors, and how this may relate to CSCs and treatment resistance, underscoring the potential for improving the efficacy of targeted therapy and immunotherapy by concurrently modulating the renin-angiotensin system.

References

Al Hmada Y, Brodell R, Kharouf N, Flanagan T, Alamodi A, Hassan S . Mechanisms of Melanoma Progression and Treatment Resistance: Role of Cancer Stem-like Cells. Cancers (Basel). 2024; 16(2). PMC: 10814963. DOI: 10.3390/cancers16020470. View

Eyler C, Rich J . Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis. J Clin Oncol. 2008; 26(17):2839-45. PMC: 2739000. DOI: 10.1200/JCO.2007.15.1829. View

Khakoo A, Sidman R, Pasqualini R, Arap W . Does the renin-angiotensin system participate in regulation of human vasculogenesis and angiogenesis?. Cancer Res. 2008; 68(22):9112-5. DOI: 10.1158/0008-5472.CAN-08-0851. View

Huang Y, Noble N, Zhang J, Xu C, Border W . Renin-stimulated TGF-beta1 expression is regulated by a mitogen-activated protein kinase in mesangial cells. Kidney Int. 2007; 72(1):45-52. DOI: 10.1038/sj.ki.5002243. View

Matsushita K, Wu Y, Okamoto Y, Pratt R, Dzau V . Local renin angiotensin expression regulates human mesenchymal stem cell differentiation to adipocytes. Hypertension. 2006; 48(6):1095-102. DOI: 10.1161/01.HYP.0000248211.82232.a7. View

Garbe C, Amaral T, Peris K, Hauschild A, Arenberger P, Basset-Seguin N . European consensus-based interdisciplinary guideline for melanoma. Part 1: Diagnostics: Update 2022. Eur J Cancer. 2022; 170:236-255. DOI: 10.1016/j.ejca.2022.03.008. View

Wang B, Zhang W, Zhang G, Kwong L, Lu H, Tan J . Targeting mTOR signaling overcomes acquired resistance to combined BRAF and MEK inhibition in BRAF-mutant melanoma. Oncogene. 2021; 40(37):5590-5599. PMC: 8445818. DOI: 10.1038/s41388-021-01911-5. View

Wang J, Nishiyama A, Matsuyama M, Wang Z, Yuan Y . The (pro)renin receptor: a novel biomarker and potential therapeutic target for various cancers. Cell Commun Signal. 2020; 18(1):39. PMC: 7060546. DOI: 10.1186/s12964-020-0531-3. View

Tawbi H, Schadendorf D, Lipson E, Ascierto P, Matamala L, Castillo Gutierrez E . Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022; 386(1):24-34. PMC: 9844513. DOI: 10.1056/NEJMoa2109970. View

10.

Farag E, Sessler D, Ebrahim Z, Kurz A, Morgan J, Ahuja S . The renin angiotensin system and the brain: New developments. J Clin Neurosci. 2017; 46:1-8. DOI: 10.1016/j.jocn.2017.08.055. View

11.

Kilmister E, Tan S . The Role of the Renin-Angiotensin System in the Cancer Stem Cell Niche. J Histochem Cytochem. 2021; 69(12):835-847. PMC: 8647629. DOI: 10.1369/00221554211026295. View

12.

Shen X, Bernstein K . The peptide network regulated by angiotensin converting enzyme (ACE) in hematopoiesis. Cell Cycle. 2011; 10(9):1363-9. PMC: 3117040. DOI: 10.4161/cc.10.9.15444. View

13.

Bi L, Okabe I, Bernard D, Wynshaw-Boris A, Nussbaum R . Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110alpha subunit of phosphoinositide 3-kinase. J Biol Chem. 1999; 274(16):10963-8. DOI: 10.1074/jbc.274.16.10963. View

14.

Hashemzehi M, Beheshti F, Hassanian S, Ferns G, Khazaei M, Avan A . Therapeutic potential of renin angiotensin system inhibitors in cancer cells metastasis. Pathol Res Pract. 2020; 216(7):153010. DOI: 10.1016/j.prp.2020.153010. View

15.

Flaherty K, Puzanov I, Kim K, Ribas A, McArthur G, Sosman J . Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010; 363(9):809-19. PMC: 3724529. DOI: 10.1056/NEJMoa1002011. View

16.

Patel S, Othus M, Chen Y, Wright Jr G, Yost K, Hyngstrom J . Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med. 2023; 388(9):813-823. PMC: 10410527. DOI: 10.1056/NEJMoa2211437. View

17.

Eggermont A, Blank C, Mandala M, Long G, Atkinson V, Dalle S . Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2021; 22(5):643-654. DOI: 10.1016/S1470-2045(21)00065-6. View

18.

Flaherty K, Robert C, Hersey P, Nathan P, Garbe C, Milhem M . Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012; 367(2):107-14. DOI: 10.1056/NEJMoa1203421. View

19.

Nakamura K, Kiniwa Y, Okuyama R . CCL5 production by fibroblasts through a local renin-angiotensin system in malignant melanoma affects tumor immune responses. J Cancer Res Clin Oncol. 2021; 147(7):1993-2001. DOI: 10.1007/s00432-021-03612-8. View

20.

Robert C, Ribas A, Schachter J, Arance A, Grob J, Mortier L . Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019; 20(9):1239-1251. DOI: 10.1016/S1470-2045(19)30388-2. View