scholarly journals Depleting RhoA/Stress Fiber-Organized Fibronectin Matrices on Tumor Cells Non-Autonomously Aggravates Fibroblast-Driven Tumor Cell Growth

2020 ◽  
Vol 21 (21) ◽  
pp. 8272
Author(s):  
Li-Tzu Huang ◽  
Chen-Lung Tsai ◽  
Shin-Huei Huang ◽  
Ming-Min Chang ◽  
Wen-Tsan Chang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Growth ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Stress Fiber ◽  
Tumor Cell Growth ◽  
Primary Tumor Growth

Fibronectin (FN) expressed by tumor cells has been known to be tumor suppressive but the pericellular FN (periFN) assembled on circulating tumor cells appears to evidently promote distant metastasis. Whereas the regulation of periFN assembly in suspended cells has currently been under investigation, how it is regulated in adherent tumor cells and the role of periFN in primary tumor growth remain elusive. Techniques of RNAi, plasmid transfections, immunoblotting, fluorescence/immunohistochemistry staining, cell proliferation assays, and primary tumor growth in C57BL6 mice and Fischer 344 rats were employed in this study. We found that endogenously synthesized FN in adherent tumor cells was required for periFN assembly which was aligned by RhoA-organized actin stress fiber (SF). Depleting periFN on adherent tumor cells congruently promoted in vivo tumor growth but surprisingly did not autonomously impact on in vitro tumor cell proliferation and apoptosis, suggestive of a non-autonomous role of periFN in in vivo tumor growth. We showed that the proliferative ability of shFN-expressing tumor cells was higher than shScramble cells did in the presence of fibroblasts. Altogether, these results suggested that depriving RhoA/SF-regulated periFN matrices non-autonomously promotes fibroblast-mediated tumor cell growth.

scholarly journals Tumor quiescence: elevating SOX2 in diverse tumor cell types downregulates a broad spectrum of the cell cycle machinery and inhibits tumor growth

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Ethan P. Metz ◽  
Erin L. Wuebben ◽  
Phillip J. Wilder ◽  
Jesse L. Cox ◽  
Kaustubh Datta ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Cell Cycle Machinery

Abstract Background Quiescent tumor cells pose a major clinical challenge due to their ability to resist conventional chemotherapies and to drive tumor recurrence. Understanding the molecular mechanisms that promote quiescence of tumor cells could help identify therapies to eliminate these cells. Significantly, recent studies have determined that the function of SOX2 in cancer cells is highly dose dependent. Specifically, SOX2 levels in tumor cells are optimized to promote tumor growth: knocking down or elevating SOX2 inhibits proliferation. Furthermore, recent studies have shown that quiescent tumor cells express higher levels of SOX2 compared to adjacent proliferating cells. Currently, the mechanisms through which elevated levels of SOX2 restrict tumor cell proliferation have not been characterized. Methods To understand how elevated levels of SOX2 restrict the proliferation of tumor cells, we engineered diverse types of tumor cells for inducible overexpression of SOX2. Using these cells, we examined the effects of elevating SOX2 on their proliferation, both in vitro and in vivo. In addition, we examined how elevating SOX2 influences their expression of cyclins, cyclin-dependent kinases (CDKs), and p27Kip1. Results Elevating SOX2 in diverse tumor cell types led to growth inhibition in vitro. Significantly, elevating SOX2 in vivo in pancreatic ductal adenocarcinoma, medulloblastoma, and prostate cancer cells induced a reversible state of tumor growth arrest. In all three tumor types, elevation of SOX2 in vivo quickly halted tumor growth. Remarkably, tumor growth resumed rapidly when SOX2 returned to endogenous levels. We also determined that elevation of SOX2 in six tumor cell lines decreased the levels of cyclins and CDKs that control each phase of the cell cycle, while upregulating p27Kip1. Conclusions Our findings indicate that elevating SOX2 above endogenous levels in a diverse set of tumor cell types leads to growth inhibition both in vitro and in vivo. Moreover, our findings indicate that SOX2 can function as a master regulator by controlling the expression of a broad spectrum of cell cycle machinery. Importantly, our SOX2-inducible tumor studies provide a novel model system for investigating the molecular mechanisms by which elevated levels of SOX2 restrict cell proliferation and tumor growth.

scholarly journals TUSC1, a Putative Tumor Suppressor Gene, Reduces Tumor Cell Growth In Vitro and Tumor Growth In Vivo

PLoS ONE ◽  
2013 ◽  
Vol 8 (6) ◽  
pp. e66114 ◽  
Author(s):  
Zhihong Shan ◽  
Abbas Shakoori ◽  
Sohrab Bodaghi ◽  
Paul Goldsmith ◽  
Jen Jin ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tumor Suppressor ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Suppressor Gene ◽  
Tumor Cell Growth ◽  
Putative Tumor Suppressor Gene ◽  
Putative Tumor Suppressor

p125 focal adhesion kinase promotes malignant astrocytoma cell proliferation in vivo

2000 ◽  
Vol 113 (23) ◽  
pp. 4221-4230 ◽  
Author(s):  
D. Wang ◽  
J.R. Grammer ◽  
C.S. Cobbs ◽  
J.E. Stewart ◽  
Z. Liu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Focal Adhesion ◽  
Fold Increase ◽  
Astrocytic Tumor ◽  
Malignant Astrocytoma

p125 focal adhesion kinase (p125FAK) is a cytoplasmic tyrosine kinase that is activated upon engagement of integrin cell adhesion receptors, and initiates several signaling events that modulate cell function in vitro. To determine the biologic role of p125FAK in malignant astrocytic tumor cells, U-251MG human malignant astrocytoma cells were stably transfected with p125FAK cDNA using the TET-ON system, and stable clones isolated that exhibited an estimated 5- or 20-fold increase in p125FAK expression on administration of 0.1 or 2.0 microg/ml doxycycline, respectively. In vitro studies demonstrated that induction of p125FAK resulted in a 2- to 3-fold increase in cell migration, increased p130CAS phosphorylation, localization of exogenous p125FAK to focal adhesions, and a 2-fold increase in soft agar growth. To determine the role of p125FAK in vivo, clones were injected stereotactically into the brains of scid mice. A 4.5-fold estimated increase in p125FAK expression was induced by administration of doxycycline in the drinking water. Analysis of xenograft brains demonstrated that, upon induction of p125FAK, there was a 1.6- to 2.8-fold increase in tumor cell number, and an increase in mAb PCNA-labeling of tumor cells in the absence of a change in the apoptotic index. Compared to normal brain, the expression of p125FAK was elevated in malignant astrocytic tumor biopsies from patient samples. These data demonstrate for the first time that p125FAK promotes tumor cell proliferation in vivo, and that the underlying mechanism is not associated with a reduction in apoptosis.

Protease Activated Receptor-1 (PAR-1) Impedes Tumor Progression

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2560-2560
Author(s):  
Gregory N. Adams ◽  
Haley Weston ◽  
Leah Rosenfeldt ◽  
Malinda Frederick ◽  
Joseph S. Palumbo
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Prostate Tumor ◽  
Protease Activated Receptor 1 ◽  
Tumor Types ◽  
And Control

Abstract Activation of cell signaling by thrombin through Protease Activated Receptor-1 (PAR-1) represents one important interface between blood coagulation and cell activation in response to injury and inflammation. In the context of cancer, PAR-1 has been suggested to promote tumor growth through mechanisms coupled to tumor cell proliferation, tumor cell migration, and the development of a supportive tumor stroma. Consistent with this view, both tumor cells and stromal cells express high levels of PAR-1, and elevated PAR-1 expression has been correlated with a poor prognosis across several tumor types. In the current studies, we tested the hypothesis that PAR-1 is a critical driver of tumorigenesis and tumor growth using murine models of genetically-induced prostate and intestinal tumor growth. To define the role of PAR-1 in prostate tumor progression, we interbred mice expressing the TRAMP transgene (transgenic adenocarcinoma of the mouse prostate; SV40 Large T antigen under the control of a probasin promoter) to PAR-1-deficient mice (PAR-1-/-) in order to generate male TRAMP mice with and without PAR-1 expression for detailed analyses of prostate tumor growth. Surprisingly, prostate tumors harvested from PAR-1-/- mice were significantly larger than those harvested from PAR-1+/+ mice. In order to begin to address the PAR-1 expressing cellular compartments responsible for prostate tumor inhibition, we subcutaneously inoculated immunocompetent C57Bl/6-derived PAR-1-/- and control mice with tumor cells derived from a C57Bl/6 TRAMP mouse. TRAMP-derived tumors grew indistinguishably in PAR-1-/- and control mice, suggesting that stromal-cell associated PAR-1 is dispensable for prostate tumor growth. We next tested the effect of tumor cell-intrinsic inhibition of PAR-1 in TRAMP tumor cells by viral transduction with a construct containing an shRNA against murine PAR-1 in parallel to a non-specific shRNA construct. Diminishing tumor cell-associated PAR-1 expression resulted in significantly more rapid tumor growth in vivo. In order to better define the role of tumor cell-intrinsic PAR-1 we harvested TRAMP tumor cells from a PAR-1 deficient mouse and grew these cells in vitro. We transduced these PAR-1-deficient prostate tumor cells with viral vectors conferring expression of WT murine PAR-1 (PAR-1+), a PAR-1 mutant lacking the thrombin cleavage (R41A mutant) or empty vector (PAR-1-). PAR-1- cells grew robustly and similarly to the parental cells in vitro with a doubling time of approximately 48 hours. Cells expressing the R41A mutant PAR-1 also grew robustly and similarly to PAR-1 deficient cells. However, PAR-1+ cells failed to show any signs of cell proliferation over the span of a 4 day observation period. Furthermore, PAR-1 expression dramatically altered the ability of TRAMP cells to demonstrate signs of cell spreading as measured by the frequency of pseudopodia per cell. As a means of determining the role of PAR-1 in tumorigenesis and tumor growth in another spontaneously occurring setting, we interbred PAR-1-/- mice with APCMin/+ mice genetically predisposed to intestinal adenoma formation due to loss of heterozygosity of the tumor suppressor adenomatous polyposis coli gene. Blinded quantitative histological analyses of the intestinal tracts of PAR-1-/- and PAR-1+/+ APCMin/+ mice revealed that PAR-1 deficiency resulted in a significant 2-fold increase in the number of adenomas observed. Furthermore, the adenomas observed in PAR-1-/- mice were significantly larger based on morphometric analyses of adenoma surface area in histological sections. In sum, these data demonstrate a surprising and unexpected role for PAR-1 in the inhibition of tumor growth in the context of two distinct tumor types. Disclosures No relevant conflicts of interest to declare.

Cyanidin 3-Glucoside and Peonidin 3-Glucoside Inhibit Tumor Cell Growth and Induce Apoptosis In Vitro and Suppress Tumor Growth In Vivo

2005 ◽  
Vol 53 (2) ◽  
pp. 232-243 ◽  
Author(s):  
Pei-Ni Chen ◽  
Shu-Chen Chu ◽  
Hui-Ling Chiou ◽  
Chui-Liang Chiang ◽  
Shun-Fa Yang ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cell Growth

scholarly journals Platelet microRNAs inhibit primary tumor growth via broad modulation of tumor cell mRNA expression in ectopic pancreatic cancer in mice

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0261633
Author(s):  
Jeremy G. T. Wurtzel ◽  
Sophia Lazar ◽  
Sonali Sikder ◽  
Kathy Q. Cai ◽  
Igor Astsaturov ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Solid Tumor ◽  
Primary Tumor ◽  
Primary Tumor Growth ◽  
Primary Tumors ◽  
Solid Tumor Growth

We investigated the contributions of platelet microRNAs (miRNAs) to the rate of growth and regulation of gene expression in primary ectopic tumors using mouse models. We previously identified an inhibitory role for platelets in solid tumor growth, mediated by tumor infiltration of platelet microvesicles (microparticles) which are enriched in platelet-derived miRNAs. To investigate the specific roles of platelet miRNAs in tumor growth models, we implanted pancreatic ductal adenocarcinoma cells as a bolus into mice with megakaryocyte-/platelet-specific depletion of mature miRNAs. We observed an ~50% increase in the rate of growth of ectopic primary tumors in these mice compared to controls including at early stages, associated with reduced apoptosis in the tumors, in particular in tumor cells associated with platelet microvesicles—which were depleted of platelet-enriched miRNAs—demonstrating a specific role for platelet miRNAs in modulation of primary tumor growth. Differential expression RNA sequencing of tumor cells isolated from advanced primary tumors revealed a broad cohort of mRNAs modulated in the tumor cells as a function of host platelet miRNAs. Altered genes comprised 548 up-regulated transcripts and 43 down-regulated transcripts, mostly mRNAs altogether spanning a variety of growth signaling pathways–notably pathways related to epithelial-mesenchymal transition—in tumor cells from platelet miRNA-deleted mice compared with those from control mice. Tumors in platelet miRNA-depleted mice showed more sarcomatoid growth and more advanced tumor grade, indicating roles for host platelet miRNAs in tumor plasticity. We further validated increased protein expression of selected genes associated with increased cognate mRNAs in the tumors due to platelet miRNA depletion in the host animals, providing proof of principle of widespread effects of platelet miRNAs on tumor cell functional gene expression in primary tumors in vivo. Together, these data demonstrate that platelet-derived miRNAs modulate solid tumor growth in vivo by broad-spectrum restructuring of the tumor cell transcriptome.

scholarly journals Mathematical Modelling of the Dynamics of Tumor Growth and its Optimal Control

2020 ◽  
Author(s):  
Jannatun Irana Ira ◽  
Md. Shahidul Islam ◽  
Jagadish Chandra Misra
Keyword(s):  
Optimal Control ◽  
Cell Growth ◽  
Tumor Growth ◽  
Mathematical Modelling ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Treatment Process ◽  
Tumor Cell Growth ◽  
Growth Of Tumor ◽  
Over Time

The dynamics of tumor cell growth and its treatment process is discussed in this paper. We analyze some simple mathematical models and generalized models to understand the growth of tumor cells. A couple of diffusion models are discussed to explain how the tumor cells spread and become more dangerous as well as the treatment process of cancer and how cancer cell behaves in the presence of different therapy and drugs. The optimal control of chemotherapy has been discussed. It has also been explained how much the model is effective in reducing tumor cells over time.

Concentration-dependent dual effect of thrombin on impaired growth/apoptosis or mitogenesis in tumor cells

Blood ◽  
2000 ◽  
Vol 95 (10) ◽  
pp. 3133-3138 ◽  
Author(s):  
Jasmine Zain ◽  
Yao-Qi Huang ◽  
XueSheng Feng ◽  
Mary Lynn Nierodzik ◽  
Jian-Jun Li ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Calf Serum ◽  
Annexin V ◽  
Tumor Cell Growth ◽  
Diisopropyl Fluorophosphate ◽  
General Caspase Inhibitor

Because thrombin-treated tumor cell-induced metastasis increases tumor nodule volume12 greater than nodule number, we studied the effect of thrombin on tumor cell growth in vitro and in vivo (murine B16F10 melanoma, human HCT8 colon carcinoma, DU145 prostate carcinoma). Tumor cell growth was measured after 3 to 7 days in 1% fetal calf serum (FCS) + RPMI 1640. We found that, whereas relatively low concentrations of thrombin, 0.1 to 0.5 U/mL (1-5 nmol/L) enhance tumor cell growth in vitro approximately 2- to 3-fold, higher concentrations, 0.5 to 1 U/mL (5-10 nmol/L) impaired cell growth approximately 2- to 4-fold. Impaired cell growth was associated with cell cycle arrest at G2M and increased pre-GoDNA, as well as apoptosis, measured by tumor cell binding to Annexin V and propidium iodide. Apoptosis was reversed with the general caspase inhibitor, FK-011. The enhancing and inhibiting effects were specific for thrombin (reversed with inactive diisopropyl-fluorophosphate [DFP]-thrombin) and mediated via the protease-activated receptor 1 (PAR-1). PAR-1 activation was demonstrated by (1) use of a cell line, B16F10, devoid of the 3 other thrombin receptors, PAR-3, PAR-4, and GPIb; and (2) greater sensitivity of PAR-1 transfected B16F10 and HCT8 cells to impaired cell growth/apoptosis, 3- and 14-fold, respectively. Thus, thrombin has a bimodal effect on PAR-1 in tumor cells: enhanced growth at low concentration, impaired growth/apoptosis at higher concentration.

scholarly journals Tumor cell-intrinsic PD-1 receptor is a tumor suppressor and mediates resistance to PD-1 blockade therapy

2020 ◽  
Vol 117 (12) ◽  
pp. 6640-6650 ◽  
Author(s):  
Xiaodong Wang ◽  
Xiaohui Yang ◽  
Chang Zhang ◽  
Yang Wang ◽  
Tianyou Cheng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Colony Formation ◽  
Immune Escape ◽  
Potential Biomarker

The programmed cell death 1 (PD-1) receptor on the surface of immune cells is an immune checkpoint molecule that mediates the immune escape of tumor cells. Consequently, antibodies targeting PD-1 have shown efficacy in enhancing the antitumor activity of T cells in some types of cancers. However, the potential effects of PD-1 on tumor cells remain largely unknown. Here, we show that PD-1 is expressed across a broad range of tumor cells. The silencing of PD-1 or its ligand, PD-1 ligand 1 (PD-L1), promotes cell proliferation and colony formation in vitro and tumor growth in vivo. Conversely, overexpression of PD-1 or PD-L1 inhibits tumor cell proliferation and colony formation. Moreover, blocking antibodies targeting PD-1 or PD-L1 promote tumor growth in cell cultures and xenografts. Mechanistically, the coordination of PD-1 and PD-L1 activates its major downstream signaling pathways including the AKT and ERK1/2 pathways, thus enhancing tumor cell growth. This study demonstrates that PD-1/PD-L1 is a potential tumor suppressor and potentially regulates the response to anti-PD-1/PD-L1 treatments, thus representing a potential biomarker for the optimal cancer immunotherapeutic treatment.

Concentration-dependent dual effect of thrombin on impaired growth/apoptosis or mitogenesis in tumor cells

Blood ◽  
2000 ◽  
Vol 95 (10) ◽  
pp. 3133-3138 ◽  
Author(s):  
Jasmine Zain ◽  
Yao-Qi Huang ◽  
XueSheng Feng ◽  
Mary Lynn Nierodzik ◽  
Jian-Jun Li ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Calf Serum ◽  
Annexin V ◽  
Tumor Cell Growth ◽  
Diisopropyl Fluorophosphate ◽  
General Caspase Inhibitor

Abstract Because thrombin-treated tumor cell-induced metastasis increases tumor nodule volume12 greater than nodule number, we studied the effect of thrombin on tumor cell growth in vitro and in vivo (murine B16F10 melanoma, human HCT8 colon carcinoma, DU145 prostate carcinoma). Tumor cell growth was measured after 3 to 7 days in 1% fetal calf serum (FCS) + RPMI 1640. We found that, whereas relatively low concentrations of thrombin, 0.1 to 0.5 U/mL (1-5 nmol/L) enhance tumor cell growth in vitro approximately 2- to 3-fold, higher concentrations, 0.5 to 1 U/mL (5-10 nmol/L) impaired cell growth approximately 2- to 4-fold. Impaired cell growth was associated with cell cycle arrest at G2M and increased pre-GoDNA, as well as apoptosis, measured by tumor cell binding to Annexin V and propidium iodide. Apoptosis was reversed with the general caspase inhibitor, FK-011. The enhancing and inhibiting effects were specific for thrombin (reversed with inactive diisopropyl-fluorophosphate [DFP]-thrombin) and mediated via the protease-activated receptor 1 (PAR-1). PAR-1 activation was demonstrated by (1) use of a cell line, B16F10, devoid of the 3 other thrombin receptors, PAR-3, PAR-4, and GPIb; and (2) greater sensitivity of PAR-1 transfected B16F10 and HCT8 cells to impaired cell growth/apoptosis, 3- and 14-fold, respectively. Thus, thrombin has a bimodal effect on PAR-1 in tumor cells: enhanced growth at low concentration, impaired growth/apoptosis at higher concentration.

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