Losartan Slows Pancreatic Tumor Progression and Extends Survival of SPARC-Null Mice by Abrogating Aberrant TGFβ Activation

Arnold, Shanna A.; Rivera, Lee B.; Carbon, Juliet G.; Toombs, Jason E.; Chang, Chi‐Lun; Bradshaw, Amy D.; Brekken, Rolf A.

doi:10.1371/journal.pone.0031384

Cited by 75 publications

(52 citation statements)

References 62 publications

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“…M2 macrophages might therefore promote tumor progression [44]. As a second possibility, Arnold and colleagues [43] speculate that the increase in local invasion could represent the response to the anti-angiogenic activity of losartan, since inhibition of angiogenesis has been shown to increase local invasion, for instance, in pancreatic cancer [45]. In the present study, we observed an increase in adhesion and invasion under in vitro conditions, i.e.…”

Section: Discussionsupporting

confidence: 59%

The Angiotensin II Type 1 Receptor Antagonist Losartan Affects NHE1-Dependent Melanoma Cell Behavior

Hofschröer

Nielsen

et al. 2018

Cell Physiol Biochem

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Background/Aims: The peptide hormone angiotensin II (ATII) plays a prominent role in regulating vasoconstriction and blood pressure. Its primary target is the angiotensin II receptor type 1 (AT₁), the stimulation of which induces an increase in cytosolic [Ca²⁺] and calmodulin activation. Ca²⁺-bound (activated) calmodulin stimulates the activity of the Na⁺/ H⁺ exchanger isoform 1 (NHE1); and increased NHE1 activity is known to promote melanoma cell motility. The competitive AT₁ receptor inhibitor losartan is often used to lower blood pressure in hypertensive patients. Since AT₁ mediates ATII-stimulated NHE1 activity, we set out to investigate whether ATII and losartan have an impact on NHE1-dependent behavior of human melanoma (MV3) cells. Methods: ATII receptor expression was verified by PCR, F-actin was visualized using fluorescently labeled phalloidin, and cytosolic [Ca²⁺] and pH were determined ratiometrically using Fura-2 and BCECF, respectively. MV3 cell behavior was analyzed using migration, adhesion, invasion and proliferation assays. Results: MV3 cells express both AT₁ and the angiotensin II receptor type 2 (AT₂). Stimulation of MV3 cells with ATII increased NHE1 activity which could be counteracted by both losartan and the Ca²⁺/ calmodulin inhibitor ophiobolin-A. ATII stimulation induced a decrease in MV3 cell migration and a more spherical cell morphology accompanied by an increase in the density of F-actin. Independently of the presence of ATII, both NHE1 and migratory activity were reduced when AT₁ was blocked by losartan. On the other hand, losartan clearly increased cell adhesion to, and the invasion of, a collagen type I substrate. The AT₂ inhibitor PD123319 did not affect NHE1 activity, proliferation and migration, but increased adhesion and invasion. Conclusion: Losartan inhibits NHE1 activity and the migration of human melanoma cells. At the same time, losartan promotes MV3 cell adhesion and invasion. The therapeutic use of AT₁ antagonists (sartans) in hypertensive cancer patients should therefore be given critical consideration.

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Section: Discussionsupporting

confidence: 59%

The Angiotensin II Type 1 Receptor Antagonist Losartan Affects NHE1-Dependent Melanoma Cell Behavior

Hofschröer

Nielsen

et al. 2018

Cell Physiol Biochem

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“…However, several more clinically relevant FDA/European Medicines Agency-approved drugs already exist for the identified targets, or candidate drugs are in advanced stages of clinical trials. Examples are losartan or neutralizing TGFb antibodies to target initial fibrotic processes, LOX antibodies to reduce crosslinking, and small molecules inhibiting FAK activity to correct mechanosensing in tumor cells and keratinocytes (11,31). Such drugs could be repurposed for rapid clinical implementation as prophylactic cSCC therapy in RDEB and other related, more common conditions.…”

Section: Discussionmentioning

confidence: 99%

Injury-Driven Stiffening of the Dermis Expedites Skin Carcinoma Progression

et al. 2016

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Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic skin fragility disorder characterized by injury-driven blister formation, progressive soft-tissue fibrosis, and a highly elevated risk of early-onset aggressive cutaneous squamous cell carcinoma (cSCC). However, the mechanisms underlying the unusually rapid progression of RDEB to cSCC are unknown. In this study, we investigated the contribution of injury-induced skin alterations to cSCC development by using a genetic model of RDEB and organotypic skin cultures. Analysis of RDEB patient samples suggested that premalignant changes to the dermal microenvironment drive tumor progression, which led us to subject a collagen VII hypomorphic mouse model of RDEB to chemical carcinogenesis. Carcinogen-treated RDEB mice developed invasive tumors phenocopying human RDEB-cSCC, whereas wild-type mice formed papillomas, indicating that the aggressiveness of RDEB-cSCC is mutation-independent. The inherent structural instability of the RDEB dermis, combined with repeated injury, increased the bioavailability of TGFb, which promoted extracellular matrix production, cross-linking, thickening of dermal fibrils, and tissue stiffening. The biophysically altered dermis increased myofibroblast activity and integrin b1/pFAK/pAKT mechanosignaling in tumor cells, further demonstrating that cSCC progression is governed by pre-existing injury-driven changes in the RDEB tissue microenvironment. Treatment of three-dimensional organotypic RDEB skin cultures with inhibitors of TGFb signaling, lysyl oxidase, or integrin b1-mediated mechanosignaling reduced or bypassed tissue stiffness and limited tumor cell invasion. Collectively, these findings provide a new mechanism by which RDEB tissue becomes malignant and offer new druggable therapeutic targets to prevent cSCC onset. Cancer Res; 76(4); 940-51. Ó2015 AACR.

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“…The reciprocal regulation of TGF-β and SPARC has been reported in many physiological and pathological contexts (20,38,64). Recent studies reported that in Sparc -/-pancreatic tumors, aberrant TGF-β activation and high levels of TGF-β were associated with decreased pericyte recruitment, destabilization of blood vessels (42,65), vascular permeability, and inflammation contributing to tumor progression (17). Our results indicate that SPARC attenuated the cancer-stromal cell crosstalk with subsequent inhibition of the inflammatory phenotype of fibroblasts and macrophages, as demonstrated by its differential effects on activation of NF-κB and AP-1 in heterotypic cocultures.…”

Section: -Isoprostane 8-oh-dg Cytokine/growth Factor Assaysmentioning

confidence: 98%

“…Use of SPARC knockout (Sparc -/-) mice revealed that SPARC suppresses syngeneic and oncogenedriven tumors (9,(11)(12)(13)(14) through regulation of matrix deposition and through antiinflammatory, antiangiogenic, antiproliferative, and proapoptotic effects, while SPARC has been found to be upregulated in the stroma (9,15). SPARC exerts autocrine and paracrine inhibition of cancer cell proliferation through cell-cycle arrest (8,9,13,16,17) and suppression of survival signaling (7,11,12,18,19), cancer cell adhesion, and invasion (8,11,12,17,18).…”

Section: Introductionmentioning

confidence: 99%

Loss of SPARC in bladder cancer enhances carcinogenesis and progression

Said¹,

Frierson²,

Sänchez‐Carbayo³

et al. 2013

J. Clin. Invest.

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Secreted protein acidic and rich in cysteine (SPARC) has been implicated in multiple aspects of human cancer. However, its role in bladder carcinogenesis and metastasis are unclear,with some studies suggesting it may be a promoter and others arguing the opposite. Using a chemical carcinogenesis model in Sparc-deficient mice and their wild-type littermates, we found that loss of SPARC accelerated the development of urothelial preneoplasia (atypia and dysplasia), neoplasia, and metastasis and was associated with decreased survival. SPARC reduced carcinogen-induced inflammation and accumulation of reactive oxygen species as well as urothelial cell proliferation. Loss of SPARC was associated with an inflammatory phenotype of tumor-associated macrophages and fibroblasts, with concomitant increased activation of urothelial and stromal NF-κB and AP1 in vivo and in vitro. Syngeneic spontaneous and experimental metastasis models revealed that tumorand stroma-derived SPARC reduced tumor growth and metastasis through inhibition of cancer-associated inflammation and lung colonization. In human bladder tumor tissues, the frequency and intensity of SPARC expression were inversely correlated with disease-specific survival. These results indicate that SPARC is produced by benign and malignant compartments of bladder carcinomas where it functions to suppress bladder carcinogenesis, progression, and metastasis.

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Losartan Slows Pancreatic Tumor Progression and Extends Survival of SPARC-Null Mice by Abrogating Aberrant TGFβ Activation

Cited by 75 publications

References 62 publications

The Angiotensin II Type 1 Receptor Antagonist Losartan Affects NHE1-Dependent Melanoma Cell Behavior

The Angiotensin II Type 1 Receptor Antagonist Losartan Affects NHE1-Dependent Melanoma Cell Behavior

Injury-Driven Stiffening of the Dermis Expedites Skin Carcinoma Progression

Loss of SPARC in bladder cancer enhances carcinogenesis and progression

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