The Role of the Renin–Angiotensin System in the Cancer Stem Cell Niche

2021 ◽  
pp. 002215542110262
Author(s):  
Ethan J. Kilmister ◽  
Swee T. Tan
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Signaling Pathways ◽  
Renin Angiotensin System ◽  
Epidemiological Data ◽  
Malignant Cells ◽  
Angiotensin System ◽  
Renin Angiotensin

Cancer stem cells (CSCs) drive metastasis, treatment resistance, and tumor recurrence. CSCs reside within a niche, an anatomically distinct site within the tumor microenvironment (TME) that consists of malignant and non-malignant cells, including immune cells. The renin–angiotensin system (RAS), a critical regulator of stem cells and key developmental processes, plays a vital role in the TME. Non-malignant cells within the CSC niche and stem cell signaling pathways such as the Wnt, Hedgehog, and Notch pathways influence CSCs. Components of the RAS and cathepsins B and D that constitute bypass loops of the RAS are expressed on CSCs in many cancer types. There is extensive in vitro and in vivo evidence showing that RAS inhibition reduces tumor growth, cell proliferation, invasion, and metastasis. However, there is inconsistent epidemiological data on the effect of RAS inhibitors on cancer incidence and survival outcomes, attributed to different patient characteristics and methodologies used between studies. Further mechanistic studies are warranted to investigate the precise effects of the RAS on CSCs directly and/or the CSC niche. Targeting the RAS, its bypass loops, and convergent signaling pathways participating in the TME and other key stem cell pathways that regulate CSCs may be a novel approach to cancer treatment:

scholarly journals Galectin-7 Impairs Placentation and Causes Preeclampsia Features in Mice

Hypertension ◽  
2020 ◽  
Vol 76 (4) ◽  
pp. 1185-1194 ◽  
Author(s):  
Ellen Menkhorst ◽  
Wei Zhou ◽  
Leilani L. Santos ◽  
Sarah Delforce ◽  
Teresa So ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
First Trimester ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Elevated Systolic Blood Pressure ◽  
System Components ◽  
Pregnant Mice ◽  
New Treatment

Preeclampsia is a serious pregnancy-induced disorder unique to humans. The etiology of preeclampsia is poorly understood; however, poor placental formation is thought causal. Galectin-7 is produced by trophoblast and is elevated in first-trimester serum of women who subsequently develop preeclampsia. We hypothesized that elevated placental galectin-7 may be causative of preeclampsia. Here, we demonstrated increased galectin-7 production in chorionic villous samples from women who subsequently develop preterm preeclampsia compared with uncomplicated pregnancies. In vitro, galectin-7 impaired human first-trimester trophoblast outgrowth, increased placental production of the antiangiogenic sFlt-1 splice variant, sFlt-1-e15a , and reduced placental production and secretion of ADAM12 (a disintegrin and metalloproteinase12) and angiotensinogen. In vivo, galectin-7 administration (E8–E12) to pregnant mice caused elevated systolic blood pressure, albuminuria, impaired placentation (reduced labyrinth vascular branching, impaired decidual spiral artery remodeling, and a proinflammatory placental state demonstrated by elevated IL1β, IL6 and reduced IL10), and dysregulated expression of renin-angiotensin system components in the placenta, decidua, and kidney, including angiotensinogen, prorenin, and the angiotensin II type 1 receptor. Collectively, this study demonstrates that elevated galectin-7 during placental formation contributes to abnormal placentation and suggests that it leads to the development of preeclampsia via altering placental production of sFlt-1 and renin-angiotensin system components. Targeting galectin-7 may be a new treatment option for preeclampsia.

scholarly journals Characterisation of cancer stem cells and the renin-angiotensin system in colon adenocarcinoma

2021 ◽  
Author(s):  
Matthew Munro
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Lines ◽  
Colon Adenocarcinoma ◽  
Renin Angiotensin System ◽  
Primary Cell ◽  
Low Grade ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Primary Cell Lines

Colorectal cancer (CRC) is the third most common cancer and the second highest cause of cancer deaths globally. More than 70% of CRC-related deaths are due to metastasis to the liver. The cancer stem cell (CSC) concept hypothesises that CSCs drive tumour growth, chemoresistance, recurrence and metastasis. Markers such as CD133, LGR5 and EpCAM, have been used to identify and isolate CSCs in CRC. However, these markers are often expressed by cells with no stem cell properties and are not expressed by all tumour-initiating cells. An improved range of markers to define CSCs is needed. In 2007, adult mouse and human fibroblasts were reprogrammed into a stem cell state and defined as induced pluripotent stem cells (iPSCs) using transcription factors OCT4, SOX2, NANOG, KLF4 and c-MYC. These genes have well-documented roles in embryonic development and the maintenance of pluripotency, and their expression has been investigated in a range of cancers. <br><br>The renin-angiotensin system (RAS) physiologically maintains blood pressure and volume and is also acknowledged to play a role in cancer. Over-expression of (pro)renin receptor (PRR), angiotensin II type 1 receptor (AT1R) and type 2 receptor (AT2R), and angiotensin-converting enzyme (ACE) have been reported in cancer. Epidemiological studies investigating the effect of RAS inhibitors on cancer outcomes have shown contradictory results.<br><br>This thesis investigates the expression of iPSC markers and RAS components in colon adenocarcinoma (CA) with three specific aims: (1) to compare CA-derived primary cell lines to their original CA tissues; (2) to investigate the expression profiles of iPSC markers in CA; and (3) to investigate expression of RAS components by CA CSCs and to determine whether CSCs can be targeted by RAS modulators. <br><br>DNA sequencing was carried out to compare the mutational profiles of formalin-fixed paraffin-embedded (FFPE) CA tissues and CA-derived cell lines to confirm whether the cell lines were a suitable in vitro model for the parent tumours.<br><br><div>Proteomics was performed to determine proteomic differences between CA tissues and patient-matched normal colon (NC) tissues, CA-derived cell lines and NC-derived cells, and between low grade CA (LGCA) tissues and cell lines and high grade CA (HGCA) tissues and cell lines. Biological processes which may link the RAS and CA were investigated, revealing enrichment of various signalling pathways that may play roles in CA onset and progression directly or via the RAS.</div><div><br></div>Western blotting and immunohistochemical staining showed elevated protein levels of OCT4, SOX2, NANOG, c-MYC, AT2R, PRR and cathepsin D in CA tissues relative to their patient-matched NC tissues, with SOX2, ACE and cathepsin B at similar levels and KLF4 less abundant in CA compared with NC tissues. Co-expression analysis by immunofluorescence staining showed a small number of epithelial cells co-expressed NANOG, SOX2, KLF4, c-MYC and CD133, as well as PRR, ACE2 and AT2R, while a small number of stromal cells co-expressed OCT4 and AT2R. This indicates the presence of at least one CSC subpopulation in CA, which expresses RAS components. HGCA tissue-derived cell lines expressed higher levels of OCT4 and SOX2 than LGCA-derived cell lines. The primary cell lines were sorted based on EpCAM expression. These EpCAM High and EpCAM Low cell subpopulations could undergo directed differentiation down the three embryonic lineages. A small number of CA-derived cells, particularly within the HGCA-derived cells, formed tumourspheres. Treatment of HGCA-derived cell lines with RAS modulators revealed that β-blockers and AT2R antagonists consistently reduced their metabolism, tumoursphere formation and iPSC marker expression. <br><br>The findings of this thesis suggest that CA-derived cell lines expressing iPSC markers have stem cell function and express RAS components. Furthermore, RAS modulators may directly influence CSCs in CA by reducing iPSC marker gene expression. This indicates a potential role for RAS modulators in regulating CSCs, which merits further investigation.

scholarly journals Impact of diminazene aceturate on renin-angiotensin system, infectious myocarditis and skeletal myositis in mice: An in vitro and in vivo study

Life Sciences ◽  
2020 ◽  
Vol 257 ◽  
pp. 118067
Author(s):  
Thaiany G. Souza-Silva ◽  
Diego F. Vilas-Boas ◽  
Elda Gonçalves-Santos ◽  
Ana Lia Mazzeti ◽  
Ivo S. Caldas ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
In Vivo Study ◽  
Diminazene Aceturate ◽  
Angiotensin System ◽  
Renin Angiotensin

scholarly journals Characterisation of cancer stem cells and the renin-angiotensin system in colon adenocarcinoma

2021 ◽  
Author(s):  
Matthew Munro
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Lines ◽  
Colon Adenocarcinoma ◽  
Renin Angiotensin System ◽  
Primary Cell ◽  
Low Grade ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Primary Cell Lines

Colorectal cancer (CRC) is the third most common cancer and the second highest cause of cancer deaths globally. More than 70% of CRC-related deaths are due to metastasis to the liver. The cancer stem cell (CSC) concept hypothesises that CSCs drive tumour growth, chemoresistance, recurrence and metastasis. Markers such as CD133, LGR5 and EpCAM, have been used to identify and isolate CSCs in CRC. However, these markers are often expressed by cells with no stem cell properties and are not expressed by all tumour-initiating cells. An improved range of markers to define CSCs is needed. In 2007, adult mouse and human fibroblasts were reprogrammed into a stem cell state and defined as induced pluripotent stem cells (iPSCs) using transcription factors OCT4, SOX2, NANOG, KLF4 and c-MYC. These genes have well-documented roles in embryonic development and the maintenance of pluripotency, and their expression has been investigated in a range of cancers. <br><br>The renin-angiotensin system (RAS) physiologically maintains blood pressure and volume and is also acknowledged to play a role in cancer. Over-expression of (pro)renin receptor (PRR), angiotensin II type 1 receptor (AT1R) and type 2 receptor (AT2R), and angiotensin-converting enzyme (ACE) have been reported in cancer. Epidemiological studies investigating the effect of RAS inhibitors on cancer outcomes have shown contradictory results.<br><br>This thesis investigates the expression of iPSC markers and RAS components in colon adenocarcinoma (CA) with three specific aims: (1) to compare CA-derived primary cell lines to their original CA tissues; (2) to investigate the expression profiles of iPSC markers in CA; and (3) to investigate expression of RAS components by CA CSCs and to determine whether CSCs can be targeted by RAS modulators. <br><br>DNA sequencing was carried out to compare the mutational profiles of formalin-fixed paraffin-embedded (FFPE) CA tissues and CA-derived cell lines to confirm whether the cell lines were a suitable in vitro model for the parent tumours.<br><br><div>Proteomics was performed to determine proteomic differences between CA tissues and patient-matched normal colon (NC) tissues, CA-derived cell lines and NC-derived cells, and between low grade CA (LGCA) tissues and cell lines and high grade CA (HGCA) tissues and cell lines. Biological processes which may link the RAS and CA were investigated, revealing enrichment of various signalling pathways that may play roles in CA onset and progression directly or via the RAS.</div><div><br></div>Western blotting and immunohistochemical staining showed elevated protein levels of OCT4, SOX2, NANOG, c-MYC, AT2R, PRR and cathepsin D in CA tissues relative to their patient-matched NC tissues, with SOX2, ACE and cathepsin B at similar levels and KLF4 less abundant in CA compared with NC tissues. Co-expression analysis by immunofluorescence staining showed a small number of epithelial cells co-expressed NANOG, SOX2, KLF4, c-MYC and CD133, as well as PRR, ACE2 and AT2R, while a small number of stromal cells co-expressed OCT4 and AT2R. This indicates the presence of at least one CSC subpopulation in CA, which expresses RAS components. HGCA tissue-derived cell lines expressed higher levels of OCT4 and SOX2 than LGCA-derived cell lines. The primary cell lines were sorted based on EpCAM expression. These EpCAM High and EpCAM Low cell subpopulations could undergo directed differentiation down the three embryonic lineages. A small number of CA-derived cells, particularly within the HGCA-derived cells, formed tumourspheres. Treatment of HGCA-derived cell lines with RAS modulators revealed that β-blockers and AT2R antagonists consistently reduced their metabolism, tumoursphere formation and iPSC marker expression. <br><br>The findings of this thesis suggest that CA-derived cell lines expressing iPSC markers have stem cell function and express RAS components. Furthermore, RAS modulators may directly influence CSCs in CA by reducing iPSC marker gene expression. This indicates a potential role for RAS modulators in regulating CSCs, which merits further investigation.

ANG II reduces net acid secretion in rat outer medullary collecting duct

2003 ◽  
Vol 285 (5) ◽  
pp. F930-F937 ◽  
Author(s):  
Susan M. Wall ◽  
Michael P. Fischer ◽  
Dawn M. Glapion ◽  
Mae De La Calzada
Keyword(s):  
Acid Secretion ◽  
Collecting Duct ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Acid Base Balance ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Medullary Collecting Duct

In rat outer medullary collecting duct (OMCD), the mechanism(s) and regulation of H+ secretion are not understood fully. The effect of changes in acid-base balance and the renin-angiotensin system on net H+ secretion was explored. Rats received NaCl, NaHCO3, NH4Cl, or nothing in their drinking water for 7 days. Total ammonia and total CO2 ( JtCO2) fluxes were measured in OMCD tubules perfused in vitro from rats in each treatment group. JtCO2 was reduced in tubules from rats drinking NH4Cl relative to those drinking NaHCO3. Because NH4Cl intake increases plasma renin and aldosterone, we asked if upregulation of the renin-angiotensin system reduces net H+ secretion. Deoxycorticosterone pivalate administered in vivo did not affect JtCO2. However, ANG II given in vivo at 0.1 ng/min reduced JtCO2 by 35%. To determine if ANG II has a direct effect on acid secretion, JtCO2 was measured with ANG II applied in vitro. ANG II (10-8 M) present in the bath solution reduced JtCO2 by 35%. This ANG II effect was not observed in the presence of the AT1 receptor blocker candesartan. In conclusion, in rat OMCD, JtCO2 is paradoxically reduced with NH4Cl ingestion. Increased circulating ANG II, as occurs during metabolic acidosis, reduces JtCO2.

Upregulation of the vascular NAD(P)H-oxidase isoforms Nox1 and Nox4 by the renin-angiotensin system in vitro and in vivo

2001 ◽  
Vol 31 (11) ◽  
pp. 1456-1464 ◽  
Author(s):  
Kirstin Wingler ◽  
Sandra Wünsch ◽  
Reinhold Kreutz ◽  
Lars Rothermund ◽  
Martin Paul ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
Angiotensin System ◽  
Renin Angiotensin

scholarly journals Regulation of sarcomagenesis by the empty spiracles homeobox genes EMX1 and EMX2

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Manuel Pedro Jimenez-García ◽  
Antonio Lucena-Cacace ◽  
Daniel Otero-Albiol ◽  
Amancio Carnero
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Transcription Factors ◽  
Neural Crest ◽  
Tumor Suppressors ◽  
Homeobox Genes ◽  
Neuronal Cell ◽  
Cell Gene Expression

AbstractThe EMX (Empty Spiracles Homeobox) genes EMX1 and EMX2 are two homeodomain gene members of the EMX family of transcription factors involved in the regulation of various biological processes, such as cell proliferation, migration, and differentiation, during brain development and neural crest migration. They play a role in the specification of positional identity, the proliferation of neural stem cells, and the differentiation of certain neuronal cell phenotypes. In general, they act as transcription factors in early embryogenesis and neuroembryogenesis from metazoans to higher vertebrates. The EMX1 and EMX2’s potential as tumor suppressor genes has been suggested in some cancers. Our work showed that EMX1/EMX2 act as tumor suppressors in sarcomas by repressing the activity of stem cell regulatory genes (OCT4, SOX2, KLF4, MYC, NANOG, NES, and PROM1). EMX protein downregulation, therefore, induced the malignance and stemness of cells both in vitro and in vivo. In murine knockout (KO) models lacking Emx genes, 3MC-induced sarcomas were more aggressive and infiltrative, had a greater capacity for tumor self-renewal, and had higher stem cell gene expression and nestin expression than those in wild-type models. These results showing that EMX genes acted as stemness regulators were reproduced in different subtypes of sarcoma. Therefore, it is possible that the EMX genes could have a generalized behavior regulating proliferation of neural crest-derived progenitors. Together, these results indicate that the EMX1 and EMX2 genes negatively regulate these tumor-altering populations or cancer stem cells, acting as tumor suppressors in sarcoma.

scholarly journals “Empowering” Cardiac Cells via Stem Cell Derived Mitochondrial Transplantation- Does Age Matter?

2021 ◽  
Vol 22 (4) ◽  
pp. 1824
Author(s):  
Matthias Mietsch ◽  
Rabea Hinkel
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Treatment Strategies ◽  
Cardiac Cells ◽  
Aging Effects ◽  
Beneficial Effects ◽  
Micro Rnas ◽  
New Treatment

With cardiovascular diseases affecting millions of patients, new treatment strategies are urgently needed. The use of stem cell based approaches has been investigated during the last decades and promising effects have been achieved. However, the beneficial effect of stem cells has been found to being partly due to paracrine functions by alterations of their microenvironment and so an interesting field of research, the “stem- less” approaches has emerged over the last years using or altering the microenvironment, for example, via deletion of senescent cells, application of micro RNAs or by modifying the cellular energy metabolism via targeting mitochondria. Using autologous muscle-derived mitochondria for transplantations into the affected tissues has resulted in promising reports of improvements of cardiac functions in vitro and in vivo. However, since the targeted treatment group represents mainly elderly or otherwise sick patients, it is unclear whether and to what extent autologous mitochondria would exert their beneficial effects in these cases. Stem cells might represent better sources for mitochondria and could enhance the effect of mitochondrial transplantations. Therefore in this review we aim to provide an overview on aging effects of stem cells and mitochondria which might be important for mitochondrial transplantation and to give an overview on the current state in this field together with considerations worthwhile for further investigations.

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