scholarly journals Cancer-associated fibroblasts actively compress cancer cells and modulate mechanotransduction

2021 ◽  
Author(s):  
Jorge Barbazan ◽  
Carlos Perez-Gonzalez ◽  
Manuel Gomez-Gonzalez ◽  
Mathieu Dedenon ◽  
Sophie Richon ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Intrinsic Property ◽  
Cancer Associated Fibroblasts ◽  
Force Transmission ◽  
Force Measurements ◽  
Cancer Cell Growth ◽  
Mechanical Signaling ◽  
Actomyosin Contractility

During tumor progression, cancer-associated fibroblasts (CAFs) accumulate in tumors and produce excessive extracellular matrix (ECM), forming a capsule that enwraps cancer cells. This capsule is a barrier that restricts tumor growth leading to the buildup of intratumoral pressure. Combining genetic and physical manipulations in vivo with microfabrication and force measurements in vitro, we found that the CAFs capsule is not a passive barrier but instead actively compresses cancer cells using actomyosin contractility. Cancer cells mechanosense CAF compression, resulting in an altered localization of the transcriptional regulator YAP. Abrogation of CAFs contractility in vivo leads to the dissipation of compressive forces and impairment of capsule formation. By mapping CAF force patterns in 3D, we show that compression is a CAF-intrinsic property independent of cancer cell growth. Supracellular coordination of CAFs is achieved through fibronectin cables that serve as scaffolds allowing force transmission. Our study unveils that the contractile capsule actively compresses cancer cells, modulates their mechanical signaling, and reorganizes tumor morphology.

Estrogen receptor β represses breast tumor growth and angiogenesis in vivo

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10101-10101
Author(s):  
J. Hartman ◽  
K. Lindberg ◽  
J. Inzunza ◽  
J. Wan ◽  
A. Ström ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Breast Tumor ◽  
Breast Cancer Cells ◽  
Cancer Cell Growth ◽  
Breast Cancer Cell Growth ◽  
Angiogenic Effect

10101 Background: Estrogens are well known stimulators of breast cancer cell growth in vitro as well as in vivo. Two different estrogen receptors exist, namely estrogen receptor (ER) α and β. ERα mediates the proliferative effect of estrogen in breast cancer cells and we have earlier shown that ERβ inhibits cell-cycle progression in vitro. Estrogens are well known stimulators of in vivo breast cancer cell growth as well as angiogenesis, and the effect is mediated through ERα. The function of ERβ in this context is not well understood. Methods: We have used ERα-positive T47D breast cancer cells stably transfected with a Tet/Off regulated ERβ expression vector system. The ERβ-inducible tumor cells are studied in vitro as well as in vivo. Results: By transplanting ERβ-inducible breast cancer cells into SCID-mice, we show that ERβ inhibits tumor growth and reduces the volume of established tumors. Furthermore, we show by immunohistochemistry, that the number of blood microvessels in the tumor periphery is decreased by ERβ expression, counteracting the well-known pro-angiogenic effect of ERα. By Western blot analysis on tumor extracts, we show that the concentration of the important pro-angiogenic growth factors VEGF and bFGF, normally expressed by breast tumor cells, is decreased in the ERβ-expressing tumors compared to the normal tumors. To exclude that the observed anti-angiogenic effect is just a result of reduced tumor growth, we incubated Tet/Off regulated ERβ expressing cells in vitro, during non-hypoxic conditions. We found that the expression of ERβ leads to decreased expression of VEGF and PDGFβ at the mRNA and protein-levels. In transient transfection assays, we found estrogen-ERα mediated up regulation of VEGF, PDGFβ and bFGF-promoter activities in T47D cells, and these activities were all suppressed following co-transfection with an ERβ-expression vector. Conclusions: We conclude that ERβ inhibits growth factor expression at transcriptional level in breast cancer cells; taken together, our data indicates that ERβ inhibits growth and angiogenesis of tumors formed by T47D breast cancer cells. This makes ERβ an interesting therapeutic target in breast cancer and perhaps treatment with the newly designed ERβ-selective ligands might work as a new anti-proliferative and anti-angiogenic therapy. No significant financial relationships to disclose.

scholarly journals Mitochondrial supercomplex assembly promotes breast and endometrial tumorigenesis by metabolic alterations and enhanced hypoxia tolerance

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Kazuhiro Ikeda ◽  
Kuniko Horie-Inoue ◽  
Takashi Suzuki ◽  
Rutsuko Hobo ◽  
Norie Nakasato ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Tricarboxylic Acid Cycle ◽  
Hypoxia Tolerance ◽  
Breast Cancer Patients ◽  
Cancer Cell Growth

Abstract Recent advance in cancer research sheds light on the contribution of mitochondrial respiration in tumorigenesis, as they efficiently produce ATP and oncogenic metabolites that will facilitate cancer cell growth. Here we show that a stabilizing factor for mitochondrial supercomplex assembly, COX7RP/COX7A2L/SCAF1, is abundantly expressed in clinical breast and endometrial cancers. Moreover, COX7RP overexpression associates with prognosis of breast cancer patients. We demonstrate that COX7RP overexpression in breast and endometrial cancer cells promotes in vitro and in vivo growth, stabilizes mitochondrial supercomplex assembly even in hypoxic states, and increases hypoxia tolerance. Metabolomic analyses reveal that COX7RP overexpression modulates the metabolic profile of cancer cells, particularly the steady-state levels of tricarboxylic acid cycle intermediates. Notably, silencing of each subunit of the 2-oxoglutarate dehydrogenase complex decreases the COX7RP-stimulated cancer cell growth. Our results indicate that COX7RP is a growth-regulatory factor for breast and endometrial cancer cells by regulating metabolic pathways and energy production.

Metformin-induced anticancer activities: recent insights

2018 ◽  
Vol 399 (4) ◽  
pp. 321-335 ◽  
Author(s):  
Stephen Safe ◽  
Vijayalekshmi Nair ◽  
Keshav Karki
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Diabetic Patients ◽  
Anticancer Activities ◽  
Cancer Cell Growth ◽  
Cell Growth And Migration ◽  
Pancreatic Cancer Cells ◽  
Underlying Mechanisms

AbstractMetformin is a widely used antidiabetic drug, and there is evidence among diabetic patients that metformin is a chemopreventive agent against multiple cancers. There is also evidence in human studies that metformin is a cancer chemotherapeutic agent, and several clinical trials that use metformin alone or in combination with other drugs are ongoing.In vivoandin vitrocancer cell culture studies demonstrate that metformin induces both AMPK-dependent and AMPK-independent genes/pathways that result in inhibition of cancer cell growth and migration and induction of apoptosis. The effects of metformin in cancer cells resemble the patterns observed after treatment with drugs that downregulate specificity protein 1 (Sp1), Sp3 and Sp4 or by knockdown of Sp1, Sp3 and Sp4 by RNA interference. Studies in pancreatic cancer cells clearly demonstrate that metformin decreases expression of Sp1, Sp3, Sp4 and pro-oncogenic Sp-regulated genes, demonstrating that one of the underlying mechanisms of action of metformin as an anticancer agent involves targeting of Sp transcription factors. These observations are consistent with metformin-mediated effects on genes/pathways in many other tumor types.

scholarly journals Arginine is an epigenetic regulator targeting TEAD4 to modulate OXPHOS in prostate cancer cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chia-Lin Chen ◽  
Sheng-Chieh Hsu ◽  
Tan-Ya Chung ◽  
Cheng-Ying Chu ◽  
Hung-Jung Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Dependent Manner ◽  
Prostate Cancer Cells ◽  
Cancer Cell Growth ◽  
Prostate Carcinogenesis ◽  
Arginine Deprivation ◽  
Epigenetic Regulator

AbstractArginine plays diverse roles in cellular physiology. As a semi-essential amino acid, arginine deprivation has been used to target cancers with arginine synthesis deficiency. Arginine-deprived cancer cells exhibit mitochondrial dysfunction, transcriptional reprogramming and eventual cell death. In this study, we show in prostate cancer cells that arginine acts as an epigenetic regulator to modulate histone acetylation, leading to global upregulation of nuclear-encoded oxidative phosphorylation (OXPHOS) genes. TEAD4 is retained in the nucleus by arginine, enhancing its recruitment to the promoter/enhancer regions of OXPHOS genes and mediating coordinated upregulation in a YAP1-independent but mTOR-dependent manner. Arginine also activates the expression of lysine acetyl-transferases and increases overall levels of acetylated histones and acetyl-CoA, facilitating TEAD4 recruitment. Silencing of TEAD4 suppresses OXPHOS functions and prostate cancer cell growth in vitro and in vivo. Given the strong correlation of TEAD4 expression and prostate carcinogenesis, targeting TEAD4 may be beneficially used to enhance arginine-deprivation therapy and prostate cancer therapy.

scholarly journals Recent Advances in Berberine Inspired Anticancer Approaches: From Drug Combination to Novel Formulation Technology and Derivatization

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1426 ◽  
Author(s):  
Solomon Habtemariam
Keyword(s):  
Cancer Cells ◽  
Direct Effect ◽  
Chemotherapeutic Agents ◽  
Cell Cycle Checkpoint ◽  
Anticancer Effect ◽  
Cancer Cell Growth ◽  
Cellular Targets ◽  
Order Of Magnitude

Berberine is multifunctional natural product with potential to treat diverse pathological conditions. Its broad-spectrum anticancer effect through direct effect on cancer cell growth and metastasis have been established both in vitro and in vivo. The cellular targets that account to the anticancer effect of berberine are incredibly large and range from kinases (protein kinase B (Akt), mitogen activated protein kinases (MAPKs), cell cycle checkpoint kinases, etc.) and transcription factors to genes and protein regulators of cell survival, motility and death. The direct effect of berberine in cancer cells is however relatively weak and occur at moderate concentration range (10–100 µM) in most cancer cells. The poor pharmacokinetics profile resulting from poor absorption, efflux by permeability-glycoprotein (P-gc) and extensive metabolism in intestinal and hepatic cells are other dimensions of berberine’s limitation as anticancer agent. This communication addresses the research efforts during the last two decades that were devoted to enhancing the anticancer potential of berberine. Strategies highlighted include using berberine in combination with other chemotherapeutic agents either to reduce toxic side effects or enhance their anticancer effects; the various novel formulation approaches which by order of magnitude improved the pharmacokinetics of berberine; and semisynthetic approaches that enhanced potency by up to 100-fold.

scholarly journals Exosomal miRNA-34 from cancer-associated fibroblasts inhibits growth and invasion of gastric cancer cells in vitro and in vivo

Aging ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 8549-8564 ◽  
Author(s):  
Liang Shi ◽  
Zhenyong Wang ◽  
Xiuchao Geng ◽  
Yuhao Zhang ◽  
Ziqing Xue
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Cancer Associated Fibroblasts ◽  
Gastric Cancer Cells ◽  
Exosomal Mirna

scholarly journals Cancer Associated Fibroblasts Promote Renal Cancer Progression Through a TDO/Kyn/AhR Dependent Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Li-bo Chen ◽  
Shun-ping Zhu ◽  
Tian-pei Liu ◽  
Heng Zhao ◽  
Ping-feng Chen ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Renal Cancer ◽  
Cancer Progression ◽  
Cancer Associated Fibroblasts ◽  
Aromatic Hydrocarbon Receptor ◽  
Cancer Migration ◽  
Tumor Tissues ◽  
Enhanced Secretion

Cancer associated fibroblasts (CAFs) play crucial roles in cancer development, however, the specific mechanisms of CAFs associated renal cancer progression remain poorly understood. Our study observed enriched CAFs in high degree malignant tumor tissues from renal cancer patients. These CAFs isolated from tumor tissues are prone to facilitate drugs resistance and promote tumor progression in vitro and in vivo. Mechanistically, CAFs up-regulated tryptophan 2, 3-dioxygenase (TDO) expression, resulting in enhanced secretion of kynurenine (Kyn). Kyn produced from CAFs could up-regulated the expression of aromatic hydrocarbon receptor (AhR), eventually resulting in the AKT and STAT3 signaling pathways activation. Inhibition of AKT signal prevented cancer cells proliferation, while inhibition of the STAT3 signal reverted drugs resistance and cancer migration induced by kynurenine. Application of AhR inhibitor DMF could efficiently suppress distant metastasis of renal cancer cells, and improve anticancer effects of sorafenib (Sor)/sunitinib (Sun), which described a promising therapeutic strategy for clinical renal cancer.

scholarly journals Searching for Promoters to Drive Stable and Long-Term Transgene Expression in Fibroblasts for Syngeneic Mouse Tumor Models

2020 ◽  
Vol 21 (17) ◽  
pp. 6098
Author(s):  
Dina V. Antonova ◽  
Irina V. Alekseenko ◽  
Anastasiia K. Siniushina ◽  
Alexey I. Kuzmich ◽  
Victor V. Pleshkan
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Transgene Expression ◽  
Close Contact ◽  
Mouse Tumor ◽  
Cancer Associated Fibroblasts

Tumor is a complex system of interactions between cancer cells and other cells of the tumor microenvironment. The cancer-associated fibroblasts (CAFs) of the tumor microenvironment remain in close contact with the cancer cells and play an important role in cancer progression. Genetically, CAFs are more stable than cancer cells, making them an attractive target for genetic modification in gene therapy. However, the efficiency of various promoters for transgene expression in fibroblasts is scarcely studied. We performed a comparative analysis of transgene long-term expression under the control of strong cytomegalovirus promoter (pCMV), constitutive cell promoter of the PCNA gene (pPCNA), and the potentially fibroblast-specific promoter of the IGFBP2 gene (pIGFBP2). In vitro expression of the transgene under the control of pCMV in fibroblasts was decreased soon after transduction, whereas the expression was more stable under the control of pIGFBP2 and pPCNA. The efficiency of transgene expression was higher under pPCNA than that under pIGFBP2. Additionally, in a mouse model, pPCNA provided more stable and increased transgene expression in fibroblasts as compared to that under pCMV. We conclude that PCNA promoter is the most efficient for long-term expression of transgenes in fibroblasts both in vitro and in vivo.

scholarly journals COL11A1 is the Key Target Gene of MIST1 on Tumor Progression of Pancreatic Cancer

2021 ◽  
Author(s):  
Yang Li ◽  
Zhiqiang Liu ◽  
Ying Sun ◽  
Dianyun Ren ◽  
Yongfeng Li ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Target Gene ◽  
Animal Experiments ◽  
Migration And Invasion ◽  
Cancer Cell Growth ◽  
Pancreatic Cancer Cells

Abstract Background: MIST1, a component of BHLH transcription factors, has been documented to be an important factor in tumor progression of pancreatic cancer, but the molecular mechanism is still unknown.Methods: COL11A1 was screened as a candidate key target gene of MIST1 in pancreatic cancer by ChIP -seq assay and verified by RT-PCR and Western Blotting on MIST1-overexpression pancreatic cancer cells. ChIP and dual-luciferase assays were performed to study the binding domain of MIST1 and COL11A1. Transwell invasion, wound healing, MTT, colony formation assays and animal experiments were performed to investigate the roles of COL11A1 expression on pancreatic cancer cells. Clinical data and TCGA datasets were used to evaluate the role of COL11A1 expression on prognosis for patients with pancreatic cancer.Results: MIST1 could bind to the promoter of COL11A1 as a negative transcription factor in pancreatic cancer. Overexpression of COL11A1 promotes pancreatic cancer cell growth, migration and invasion in vitro and in vivo. Expression of COL11A1 was upregulated in pancreatic cancer and positively correlated with a worse prognosis for patients with pancreatic cancer. Conclusions: These results demonstrated COL11A1 as a carcinogen in pancreatic cancer, and it acts as the key target gene of MIST1 on tumor progression of pancreatic cancer. COL11A1 can act as a potential therapeutic target of pancreatic cancer which is superior to MIST1.

scholarly journals WWOX Possesses N-Terminal Cell Surface-Exposed Epitopes WWOX7-21 and WWOX7-11 for Signaling Cancer Growth Suppression and Prevention In Vivo

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1818 ◽  
Author(s):  
Wan-Jen Wang ◽  
Pei-Chuan Ho ◽  
Ganesan Nagarajan ◽  
Yu-An Chen ◽  
Hsiang-Ling Kuo ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cell Membrane ◽  
Cancer Cells ◽  
Specific Antibody ◽  
Time Lapse ◽  
Growth Suppression ◽  
Cancer Growth ◽  
Cancer Cell Growth

Membrane hyaluronidase Hyal-2 supports cancer cell growth. Inhibition of Hyal-2 by specific antibody against Hyal-2 or pY216-Hyal-2 leads to cancer growth suppression and prevention in vivo. By immunoelectron microscopy, tumor suppressor WWOX is shown to be anchored, in part, in the cell membrane by Hyal-2. Alternatively, WWOX undergoes self-polymerization and localizes in the cell membrane. Proapoptotic pY33-WWOX binds Hyal-2, and TGF-β induces internalization of the pY33-WWOX/Hyal-2 complex to the nucleus for causing cell death. In contrast, when pY33 is downregulated and pS14 upregulated in WWOX, pS14-WWOX supports cancer growth in vivo. Here, we investigated whether membrane WWOX receives extracellular signals via surface-exposed epitopes, especially at the S14 area, that signals for cancer growth suppression and prevention. By using a simulated 3-dimentional structure and generated specific antibodies, WWOX epitopes were determined at amino acid #7 to 21 and #286 to 299. Synthetic WWOX7-21 peptide, or truncation to 5-amino acid WWOX7-11, significantly suppressed and prevented the growth and metastasis of melanoma and skin cancer cells in mice. Time-lapse microscopy revealed that WWOX7-21 peptide potently enhanced the explosion and death of 4T1 breast cancer stem cell spheres by ceritinib. This is due to rapid upregulation of proapoptotic pY33-WWOX, downregulation of prosurvival pERK, prompt increases in Ca2+ influx, and disruption of the IkBα/WWOX/ERK prosurvival signaling. In contrast, pS14-WWOX7-21 peptide dramatically increased cancer growth in vivo and protected cancer cells from ceritinib-mediated apoptosis in vitro, due to a prolonged ERK phosphorylation. Further, specific antibody against pS14-WWOX significantly enhanced the ceritinib-induced apoptosis. Together, the N-terminal epitopes WWOX7-21 and WWOX7-11 are potent in blocking cancer growth in vivo. WWOX7-21 and WWOX7-11 peptides and pS14-WWOX antibody are of therapeutic values in suppressing and preventing cancer growth in vivo.

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