scholarly journals BSCI-10. Invasive growth of brain metastases is driven by cancer cell-pSTAT3+ reactive astrocyte crosstalk

2021 ◽  
Vol 3 (Supplement_3) ◽  
pp. iii3-iii3
Author(s):  
Matthew Dankner ◽  
Sarah Maritan ◽  
Rebecca Zhuang ◽  
Maxime Caron ◽  
Neibla Priego ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Cancer Cell ◽  
Cell Invasion ◽  
Brain Slice ◽  
Invasive Growth ◽  
Cancer Cell Invasion ◽  
Genetic Ablation ◽  
Brain Slice Cultures ◽  
Stat3 Inhibition

Abstract Background Brain metastases (BrM) with a highly invasive (HI) histological growth pattern are associated with poor prognosis compared to minimally invasive (MI) masses. Compared to MI lesions, HI BrM form greater contacts with cells in the peritumoral brain, particularly reactive astrocytes (RAs). RAs expressing phosphorylated STAT3 (pSTAT3+RAs) have been shown to promote BrM colonization. Here, we investigate the role of pSTAT3+RAs in promoting invasive growth of HI BrM. Methods We performed immunohistochemistry to identify pSTAT3+RAs in HI and MI human and patient-derived xenograft BrM. We assessed how pharmacological STAT3 inhibition or RA-specific STAT3 genetic ablation affected HI and MI BrM growth in vivo. scRNA-seq data generated from HI BrM astrocytes were integrated with published RA secretome data to identify STAT3 targets expressed by RAs that may drive invasion. Cancer cell invasion was modeled in vitro using a brain slice-tumor co-culture assay. Results HI BrM display increased pSTAT3-positivity within RAs when compared to MI lesions. Pharmacological STAT3 inhibition with Legasil (Silibinin) or genetic ablation decreased in vivo growth of HI, but not MI, BrM. Brain slice cultures treated with STAT3-activating cytokines induced cancer cell invasion, a response that was ablated following STAT3 inhibition. Chi3L1 was identified as a STAT3 target expressed by RAs. Cancer cells treated with recombinant Chi3L1 showed greater invasion into brain slice cultures compared to untreated cells. Conclusions pSTAT3+RAs are over-represented in HI BrM, rendering HI BrM preferentially sensitive to STAT3 inhibition. pSTAT3+RAs functionally contribute to BrM invasion within the brain, in part through Chi3L1-mediated activity. This work identifies STAT3 and Chi3L1 as clinically relevant therapeutic targets in management of HI BrM.

scholarly journals Quantitative real-time imaging of molecular dynamics during cancer cell invasion and metastasis in vivo

2009 ◽  
Vol 3 (4) ◽  
pp. 351-354 ◽  
Author(s):  
Paul Timpson ◽  
Alan Serrels ◽  
Marta Canel ◽  
Margaret C. Frame ◽  
Valerie G. Brunton ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Real Time ◽  
Cancer Cell ◽  
Cell Invasion ◽  
Cancer Cell Invasion ◽  
Invasion And Metastasis ◽  
Real Time Imaging

scholarly journals 3-Bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate inhibits cancer cell invasion in vitro and tumour growth in vivo

2003 ◽  
Vol 88 (7) ◽  
pp. 1111-1118 ◽  
Author(s):  
I Kempen ◽  
D Papapostolou ◽  
N Thierry ◽  
L Pochet ◽  
S Counerotte ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Cell Invasion ◽  
Tumour Growth ◽  
Cancer Cell Invasion

scholarly journals Erratum: OTUB1 de-ubiquitinating enzyme promotes prostate cancer cell invasion in vitro and tumorigenesis in vivo

2015 ◽  
Vol 14 (1) ◽  
Author(s):  
Diego Iglesias-Gato ◽  
Yin-Choy Chuan ◽  
Ning Jiang ◽  
Charlotte Svensson ◽  
Jing Bao ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cell ◽  
Cell Invasion ◽  
Prostate Cancer Cell ◽  
Cancer Cell Invasion

scholarly journals Targeting androgen receptor (AR) with antiandrogen Enzalutamide increases prostate cancer cell invasion yet decreases bladder cancer cell invasion via differentially altering the AR/circRNA-ARC1/miR-125b-2-3p or miR-4736/PPARγ/MMP-9 signals

2021 ◽  
Author(s):  
Gang Deng ◽  
Ronghao Wang ◽  
Yin Sun ◽  
Chi-Ping Huang ◽  
Shuyuan Yeh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bladder Cancer ◽  
Androgen Receptor ◽  
Cancer Cell ◽  
Cell Invasion ◽  
Preclinical Study ◽  
Circular Rnas ◽  
Cancer Cell Invasion

AbstractAndrogen-deprivation therapy (ADT) via targeting androgens/androgen receptor (AR) signals may suppress cell proliferation in both prostate cancer (PCa) and bladder cancer (BCa), yet its impact on the cell invasion of these two urological cancers remains unclear. Here we found targeting androgens/AR with either the recently developed antiandrogen Enzalutamide (Enz) or AR-shRNAs led to increase PCa cell invasion, yet decrease BCa cell invasion. Mechanistic dissection revealed that suppressing androgens/AR signals could result in differential alterations of the selective circular RNAs (circRNAs) as a result of differential endogenous AR transcription. A negative autoregulation in PCa, yet a positive autoregulation in BCa, as a result of differential binding of AR to different androgen-response elements (AREs) and a discriminating histone H3K4 methylation, likely contributes to this outcome between these two urological tumors. Further mechanistic studies indicated that AR-encoded circRNA-ARC1 might sponge/alter the availability of the miRNAs miR-125b-2-3p and/or miR-4736, to impact the metastasis-related PPARγ/MMP-9 signals to alter the PCa vs. BCa cell invasion. The preclinical study using the in vivo mouse model confirms in vitro cell lines data, showing that Enz treatment could increase PCa metastasis, which can be suppressed after suppressing circRNA-ARC1 with sh-circRNA-ARC1. Together, these in vitro/in vivo results demonstrate that antiandrogen therapy with Enz via targeting AR may lead to either increase PCa cell invasion or decrease BCa cell invasion. Targeting these newly identified AR/circRNA-ARC1/miR-125b-2-3p and/or miR-4736/PPARγ/MMP-9 signals may help in the development of new therapies to better suppress the Enz-altered PCa vs. BCa metastasis.

scholarly journals Tumoral Neuroligin 1 Promotes Cancer–Nerve Interactions and Synergizes with the Glial Cell Line-Derived Neurotrophic Factor

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 280
Author(s):  
Laura Bizzozero ◽  
Margherita Pergolizzi ◽  
Davide Pascal ◽  
Elena Maldi ◽  
Giulia Villari ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Line ◽  
Glial Cell ◽  
Cancer Cell ◽  
Cell Invasion ◽  
Neurotrophic Factor ◽  
Regulatory Protein ◽  
Cancer Cell Invasion

Many nervous proteins are expressed in cancer cells. In this report, we asked whether the synaptic protein neuroligin 1 (NLGN1) was expressed by prostatic and pancreatic carcinomas; in addition, given the tendency of these tumors to interact with nerves, we asked whether NLGN1 played a role in this process. Through immunohistochemistry on human tissue microarrays, we showed that NLGN1 is expressed by prostatic and pancreatic cancer tissues in discrete stages and tumor districts. Next, we performed in vitro and in vivo assays, demonstrating that NLGN1 promotes cancer cell invasion and migration along nerves. Because of the established role of the neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) in tumor–nerve interactions, we assessed a potential NLGN1–GDNF cooperation. We found that blocking GDNF activity with a specific antibody completely inhibited NLGN1-induced in vitro cancer cell invasion of nerves. Finally, we demonstrated that, in the presence of NLGN1, GDNF markedly activates cofilin, a cytoskeletal regulatory protein, altering filopodia dynamics. In conclusion, our data further prove the existence of a molecular and functional cross-talk between the nervous system and cancer cells. NLGN1 was shown here to function along one of the most represented neurotrophic factors in the nerve microenvironment, possibly opening new therapeutic avenues.

scholarly journals Protein kinase D2 induces invasion of pancreatic cancer cells by regulating matrix metalloproteinases

2014 ◽  
Vol 25 (3) ◽  
pp. 324-336 ◽  
Author(s):  
Christoph Wille ◽  
Conny Köhler ◽  
Milena Armacki ◽  
Arsia Jamali ◽  
Ulrike Gössele ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Extracellular Matrix ◽  
Protein Kinase ◽  
Cancer Cell ◽  
Cell Invasion ◽  
Pancreatic Cancer Cell ◽  
Therapeutic Strategies ◽  
Cancer Cell Invasion ◽  
Pancreatic Cancer Cells

Pancreatic cancer cell invasion, metastasis, and angiogenesis are major challenges for the development of novel therapeutic strategies. Protein kinase D (PKD) isoforms are involved in controlling tumor cell motility, angiogenesis, and metastasis. In particular PKD2 expression is up-regulated in pancreatic cancer, whereas PKD1 expression is lowered. We report that both kinases control pancreatic cancer cell invasive properties in an isoform-specific manner. PKD2 enhances invasion in three-dimensional extracellular matrix (3D-ECM) cultures by stimulating expression and secretion of matrix metalloproteinases 7 and 9 (MMP7/9), by which MMP7 is likely to act upstream of MMP9. Knockdown of MMP7/9 blocks PKD2-mediated invasion in 3D-ECM assays and in vivo using tumors growing on chorioallantois membranes. Furthermore, MMP9 enhances PKD2-mediated tumor angiogenesis by releasing extracellular matrix–bound vascular endothelial growth factor A, increasing its bioavailability and angiogenesis. Of interest, specific knockdown of PKD1 in PKD2-expressing pancreatic cancer cells further enhanced the invasive properties in 3D-ECM systems by generating a high-motility phenotype. Loss of PKD1 thus may be beneficial for tumor cells to enhance their matrix-invading abilities. In conclusion, we define for the first time PKD1 and 2 isoform–selective effects on pancreatic cancer cell invasion and angiogenesis, in vitro and in vivo, addressing PKD isoform specificity as a major factor for future therapeutic strategies.

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