Journal articles on the topic 'Cancer and invasion'
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Doak, Andrea E., Rose Qu, and Kevin J. Cheung. "Abstract A014: Transcriptional regulation of basal leader cell identity during collective breast cancer invasion." Cancer Research 83, no. 2_Supplement_2 (January 15, 2023): A014. http://dx.doi.org/10.1158/1538-7445.metastasis22-a014.
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Abstract An early step in breast cancer progression is invasion of tumor cells into surrounding tissues. In many breast cancers, particularly ductal carcinomas, this invasion is accomplished by tumor cells migrating as a cohesive group. This often involves cells that take on heterogeneous roles as either leader or follower cells. Studies in common mouse and human breast cancer models have established that leader cells express high levels of keratin-14 (K14) and other basal epithelial markers. The presence of these K14+ cells promote metastasis and predict poor prognosis. The molecular mechanisms regulating K14+ leader cell identity and the methods for targeted depletion of these cells remain obscure. Here we performed time-sampled single cell RNA-sequencing in 3D type I collagen-embedded tumor organoids isolated from the MMTV-PyMT luminal B model of breast cancer. 11 distinct cellular transcriptional states were identified, and through correlation with K14 expression and invasive strand formation we classified one of the states as leader cells. Having confirmed the leader cell cluster markers spatially localize to the invasive front, we next asked which transcription factors were enriched, reasoning that transcription factors could be master regulators of leader cell fate. Three different shRNAs targeting ten genes were systematically evaluated for their effects on collective invasion and keratin-14 transcription. Each transcription factor was designated as either an invasion promoter or invasion suppressor depending on the correlation between transcription factor expression and organoid invasion. Studies are ongoing investigating the impact of invasion-promoting and invasion-suppressing transcription factors on cellular transcriptional states and metastatic dissemination in-vivo. We propose that targeting invasion-suppressing pathways could be combined with therapies that specifically target and eliminate K14+ invasive cells. To this end, we have identified multiple candidate druggable targets and specific surface markers expressed in K14+ invasive cells. Citation Format: Andrea E. Doak, Rose Qu, Kevin J. Cheung. Transcriptional regulation of basal leader cell identity during collective breast cancer invasion [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A014.
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Hirano, Kazuki, Kosuke Nomura, Dan Nobuhiro, Masami Tanaka, Junichiro Sato, Akira Matsui, Shusuke Haruta, Daisuke Kikuchi, and Shu Hoteya. "A rare case of Helicobacter pylori–uninfected foveolar-type gastric cancer with submucosal invasion and lymph node metastasis." SAGE Open Medical Case Reports 10 (January 2022): 2050313X2211116. http://dx.doi.org/10.1177/2050313x221111673.
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Gastric cancer without Helicobacter pylori infection accounts for less than 1% of all gastric cancers, and is generally considered to be less invasive. This report describes a rare case of H. pylori–uninfected gastric cancer with deep submucosal invasion and lymph node metastasis. Endoscopic submucosal dissection was performed, and pathological examination revealed tubular adenocarcinoma with deep submucosal invasion. We diagnosed foveolar-type gastric adenocarcinoma. While many cases of foveolar-type gastric adenocarcinoma, especially of the white elevated type, are reported as early stage gastric cancer, this case is very rare because it showed submucosal invasion and lymph node metastasis.
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Carr, I., M. Levy, and P. Watson. "The invasive edge: invasion in colorectal cancer." Clinical & Experimental Metastasis 4, no. 2 (1986): 129–39. http://dx.doi.org/10.1007/bf00119079.
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Zhu, Shoumin, Abbes Belkhiri, and Wael El-Rifai. "Induction of MT1-MMP expression and enhancement of gastric cancer cells invasion by DARPP-32-CXCR4 interaction." Journal of Clinical Oncology 31, no. 4_suppl (February 1, 2013): 14. http://dx.doi.org/10.1200/jco.2013.31.4_suppl.14.
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14 Background: Dopamine and cAMP-regulated phosphoprotein, Mr 32000 (DARPP-32) is amplified and overexpressed in approximately 70% of gastric cancers. The prognosis for gastric cancer patients remains poor, especially in more advanced stages. Recently, it was suggested that CXCL-12 and its receptor, CXCR4, are involved in gastric cancer metastasis. However, the detailed mechanism of gastric cancer metastasis is still not completely understood. Methods: Cells invasive activity was determined by invasion assay and HUVEC invasion assay. The association between DARPP-32 and CXCR4 was evaluated by immunofluorescence and co-immunoprecipitation assays. CXCR4 degradation was analyzed by Ubiquitination Assay. Results: Overexpression of DARPP-32 in AGS cells increased cell invasion with about as three-fold invasive cells as the vector control (p<0.01). As measured by HUVEC invasion assay, overexpression of DARPP-32 in AGS cells also had a significant increase in the invasive activity (p<0.001). We found that DARPP-32 led to increased CXCR4 and MT1-MMP protein levels in DARPP-32 expressing AGS cells. The co-immunoprecipitation and immunofluorescence experiments demonstrated the existence of DARPP-32 and CXCR4 in the same protein complex. AGS cells expressing DARPP-32 displayed stable protein levels of CXCR4. IP-Western blot showed reduced ubiquitination of CXCR4 protein following the overexpression of DARPP-32 and treatment with CXCL-12, as compared to controls. Using AMD3100 (0.2 ng/ml) overnight blocked DARPP-32-induced cell invasion. The knockdown of endogenous DARPP-32 by lentiviral DARPP-32 shRNA in MKN-45 cell line reversed these signaling effects and decreased cell invasive activity, as measured by invasion and HUVEC invasion Assay (p<0.01, p<0.05). Conclusions: The in vitro studies indicate that DARPP-32 plays a role in invasion and metastasis; DARPP-32 promotes invasion and metastasis of gastric cancer cells by interacted with CXCR4, delaying CXCL-12-induced CXCR4 Ubiquitination and blocking CXCR4 degradation, activating MMP2 by increasing MT1-MMP expression. The in vivo experiments are ongoing to determine the efficacy of DARPP-32 in mediating CXCR4 overexpression and metastasis.
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Hansen, Malene Bredahl, Maria Postol, Siri Tvingsholm, Inger Ødum Nielsen, Tiina Naumanen Dietrich, Pietri Puustinen, Kenji Maeda, et al. "Identification of lysosome‐targeting drugs with anti‐inflammatory activity as potential invasion inhibitors of treatment resistant HER2 positive cancers." Cellular Oncology 44, no. 4 (May 3, 2021): 805–20. http://dx.doi.org/10.1007/s13402-021-00603-2.
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Abstract Purpose Most HER2 positive invasive cancers are either intrinsic non-responsive or develop resistance when treated with 1st line HER2 targeting drugs. Both 1st and 2nd line treatments of HER2 positive cancers are aimed at targeting the HER2 receptor directly, thereby strongly limiting the treatment options of HER2/ErbB2 inhibition resistant invasive cancers. Methods We used phenotypic high throughput microscopy screening to identify efficient inhibitors of ErbB2-induced invasion using 1st line HER2 inhibitor trastuzumab- and pertuzumab-resistant, p95-ErbB2 expressing breast cancer cells in conjunction with the Prestwick Chemical Library®. The screening entailed a drug’s ability to inhibit ErbB2-induced, invasion-promoting positioning of lysosomes at the cellular periphery, a phenotype that defines their invasiveness. In addition, we used high throughput microscopy and biochemical assays to assess the effects of the drugs on lysosomal membrane permeabilization (LMP) and autophagy, two features connected to cancer treatment. Using 2nd line HER2 inhibitor lapatinib resistant 3-dimensional model systems, we assessed the effects of the drugs on ErbB2 positive breast cancer spheroids and developed a high-throughput invasion assay for HER2 positive ovarian cancer organoids for further evaluation. Results We identified Auranofin, Colchicine, Monensin, Niclosamide, Podophyllotoxin, Quinacrine and Thiostrepton as efficient inhibitors of invasive growth of 2nd line HER2 inhibitor lapatinib resistant breast cancer spheroids and ovarian cancer organoids. We classified these drugs into four groups based on their ability to target lysosomes by inducing autophagy and/or LMP, i.e., drugs inducing early LMP, early autophagy with late LMP, late LMP, or neither. Conclusions Our results indicate that targetable lysosome-engaging cellular pathways downstream of ErbB2 contribute to invasion. They support lysosomal trafficking as an attractive target for therapy aiming at preventing the spreading of cancer cells. Since these drugs additionally possess anti-inflammatory activities, they could serve as multipurpose drugs simultaneously targeting infection/inflammation and cancer spreading.
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Rossi, Fabiana Alejandra, Ezequiel Hernán Calvo Roitberg, Juliana Haydeé Enriqué Steinberg, Molishree Umesh Joshi, Joaquín Maximiliano Espinosa, and Mario Rossi. "HERC1 Regulates Breast Cancer Cells Migration and Invasion." Cancers 13, no. 6 (March 15, 2021): 1309. http://dx.doi.org/10.3390/cancers13061309.
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Tumor cell migration and invasion into adjacent tissues is one of the hallmarks of cancer and the first step towards secondary tumors formation, which represents the leading cause of cancer-related deaths. This process is considered an unmet clinical need in the treatment of this disease, particularly in breast cancers characterized by high aggressiveness and metastatic potential. To identify and characterize genes with novel functions as regulators of tumor cell migration and invasion, we performed a genetic loss-of-function screen using a shRNA library directed against the Ubiquitin Proteasome System (UPS) in a highly invasive breast cancer derived cell line. Among the candidates, we validated HERC1 as a gene regulating cell migration and invasion. Furthermore, using animal models, our results indicate that HERC1 silencing affects primary tumor growth and lung colonization. Finally, we conducted an in silico analysis using publicly available protein expression data and observed an inverse correlation between HERC1 expression levels and breast cancer patients’ overall survival. Altogether, our findings demonstrate that HERC1 might represent a novel therapeutic target for the development or improvement of breast cancer treatment.
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Nagai, Tomoaki, Tomohiro Ishikawa, Yasuhiro Minami, and Michiru Nishita. "Tactics of cancer invasion: solitary and collective invasion." Journal of Biochemistry 167, no. 4 (January 11, 2020): 347–55. http://dx.doi.org/10.1093/jb/mvaa003.
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Abstract Much attention has been paid on the mechanism of cancer invasion from the viewpoint of the behaviour of individual cancer cells. On the other hand, histopathological analyses of specimens from cancer patients and of cancer invasion model animals have revealed that cancer cells often exhibit collective invasion, characterized by sustained cell-to-cell adhesion and polarized invasion as cell clusters. Interestingly, it has recently become evident that during collective invasion of cancer cells, the cells localized at invasion front (leader cells) and the cells following them (follower cells) exhibit distinct cellular characteristics, and that there exist the cells expressing representative proteins related to both epithelial and mesenchymal properties simultaneously, designated as hybrid epithelial-to-mesenchymal transition (EMT)-induced cells, in cancer tissue. Furthermore, the findings that cells adopted in hybrid EMT state form clusters and show collective invasion in vitro emphasize an importance of hybrid EMT-induced cells in collective cancer invasion. In this article, we overview recent findings of the mechanism underlying collective invasion of cancer cells and discuss the possibility of controlling cancer invasion and metastasis by targeting this process.
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Yanagisawa, Kiminori, Masamitsu Konno, Hao Liu, Shinji Irie, Tsunekazu Mizushima, Masaki Mori, Yuichiro Doki, Hidetoshi Eguchi, Michiya Matsusaki, and Hideshi Ishii. "A Four-Dimensional Organoid System to Visualize Cancer Cell Vascular Invasion." Biology 9, no. 11 (October 27, 2020): 361. http://dx.doi.org/10.3390/biology9110361.
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Vascular invasion of cancer is a critical step in cancer progression, but no drug has been developed to inhibit vascular invasion. To achieve the eradication of cancer metastasis, elucidation of the mechanism for vascular invasion and the development of innovative treatment methods are required. Here, a simple and reproducible vascular invasion model is established using a vascular organoid culture in a fibrin gel with collagen microfibers. Using this model, it was possible to observe and evaluate the cell dynamics and histological positional relationship of invasive cancer cells in four dimensions. Cancer-derived exosomes promoted the vascular invasion of cancer cells and loosened tight junctions in the vascular endothelium. As a new evaluation method, research using this vascular invasion mimic model will be advanced, and applications to the evaluation of the vascular invasion suppression effect of a drug are expected.
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Evans, Douglas M., and Kimberly Sloan-Stakleff. "Suppression of the Invasive Capacity of Human Breast Cancer Cells by Inhibition of Urokinase Plasminogen Activator via Amiloride and B428." American Surgeon 66, no. 5 (May 2000): 460–64. http://dx.doi.org/10.1177/000313480006600507.
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Inhibition of urokinase plasminogen activator (uPA) has been shown to suppress cancer cell invasion and metastasis in the laboratory setting by numerous investigators. Most studies have used murine cell lines implanted in syngeneic rodents or transfected human cell lines grown in immunocompromised laboratory hosts. In this study using Matrigel invasion chambers and two separate uPA inhibitors, amiloride and B428, the invasive capacity of unaltered human breast cancer cells was significantly suppressed. Cell proliferation was also suppressed to a lesser degree. These findings suggest that uPA inhibition may be a valid clinical approach to the control of the invasion and metastasis of human cancers.
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Cooper, Harry S. "Pathologic Issues in the Treatment of Endoscopically Removed Malignant Colorectal Polyps." Journal of the National Comprehensive Cancer Network 5, no. 9 (October 2007): 991–96. http://dx.doi.org/10.6004/jnccn.2007.0083.
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Endoscopically removed malignant colorectal polyps are early stage cancers for which treatment depends on histopathologic findings. For accurate pathologic evaluation, the polyps should be received in 1 piece because margins cannot be accurately assessed in fragmented polyps. Polyps with grade I or II cancer, no lymphovascular invasion, and a negative resection margin can be successfully treated with endoscopic polypectomy, whereas those with grade III cancer, lymphovascular invasion, or a positive or close margin require definitive surgical resection after endoscopic polypectomy. Potentially new significant parameters for patient management are depth of invasion and tumor budding. The pathology report must be clear and concise, indicating all relevant important parameters. The pathologist must differentiate invasive adenocarcinoma from intramucosal adenocarcinoma and pseudo-invasion.
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Gerashchenko, Tatiana S., Nikita M. Novikov, Nadezhda V. Krakhmal, Sofia Y. Zolotaryova, Marina V. Zavyalova, Nadezhda V. Cherdyntseva, Evgeny V. Denisov, and Vladimir M. Perelmuter. "Markers of Cancer Cell Invasion: Are They Good Enough?" Journal of Clinical Medicine 8, no. 8 (July 24, 2019): 1092. http://dx.doi.org/10.3390/jcm8081092.
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Invasion, or directed migration of tumor cells into adjacent tissues, is one of the hallmarks of cancer and the first step towards metastasis. Penetrating to adjacent tissues, tumor cells form the so-called invasive front/edge. The cellular plasticity afforded by different kinds of phenotypic transitions (epithelial–mesenchymal, collective–amoeboid, mesenchymal–amoeboid, and vice versa) significantly contributes to the diversity of cancer cell invasion patterns and mechanisms. Nevertheless, despite the advances in the understanding of invasion, it is problematic to identify tumor cells with the motile phenotype in cancer tissue specimens due to the absence of reliable and acceptable molecular markers. In this review, we summarize the current information about molecules such as extracellular matrix components, factors of epithelial–mesenchymal transition, proteases, cell adhesion, and actin cytoskeleton proteins involved in cell migration and invasion that could be used as invasive markers and discuss their advantages and limitations. Based on the reviewed data, we conclude that future studies focused on the identification of specific invasive markers should use new models one of which may be the intratumor morphological heterogeneity in breast cancer reflecting different patterns of cancer cell invasion.
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Suhail, Yasir, Junaid Afzal, and Kshitiz. "Evolved Resistance to Placental Invasion Secondarily Confers Increased Survival in Melanoma Patients." Journal of Clinical Medicine 10, no. 4 (February 5, 2021): 595. http://dx.doi.org/10.3390/jcm10040595.
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Mammals exhibit large differences in rates of cancer malignancy, even though the tumor formation rates may be similar. In placental mammals, rates of malignancy correlate with the extent of placental invasion. Our Evolved Levels of Invasibility (ELI) framework links these two phenomena identifying genes that potentially confer resistance in stromal fibroblasts to limit invasion, from trophoblasts in the endometrium, and from disseminating melanoma in the skin. Herein, using patient data from The Cancer Genome Atlas (TCGA), we report that these anti-invasive genes may be crucial in melanoma progression in human patients, and that their loss is correlated with increased cancer spread and lowered survival. Our results suggest that, surprisingly, these anti-invasive genes, which have lower expression in humans compared to species with non-invasive placentation, may potentially prevent stromal invasion, while a further reduction in their levels increases the malignancy and lethality of melanoma. Our work links evolution, comparative biology, and cancer progression across tissues, indicating new avenues for using evolutionary medicine to prognosticate and treat human cancers.
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Seifi, Farinaz, Vinita Parkash, Mitchell Clark, Gulden Menderes, Christina Tierney, Dan-Arin Silasi, and Masoud Azodi. "Pseudovascular Invasion: Minimally Invasive Surgery for Endometrial Cancer." JSLS : Journal of the Society of Laparoendoscopic Surgeons 23, no. 2 (2019): e2019.00021. http://dx.doi.org/10.4293/jsls.2019.00021.
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Ubukata, Yasunari, Kyoichi Ogata, Makoto Sohda, Takehiko Yokobori, Yuki Shimoda, Tadashi Handa, Nobuhiro Nakazawa, et al. "Role of PD-L1 Expression during the Progression of Submucosal Gastric Cancer." Oncology 99, no. 1 (October 28, 2020): 15–22. http://dx.doi.org/10.1159/000509033.
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<b><i>Introduction:</i></b> Programmed death-ligand 1 (PD-L1) expression is a prognostic marker for gastric cancer that correlates with tumor diameter and depth of penetration. But the role of PD-L1 and mechanism(s) employed in the initial phase of invasion in early gastric cancer is yet to be understood. <b><i>Objective:</i></b> This study aims to elucidate the role of PD-L1 during the progression of gastric cancer, specifically invading the submucosa beyond the lamina muscularis mucosa. <b><i>Methods:</i></b> Using 107 patients with pathological submucosal gastric cancer, we determined the expression of PD-L1 based on the staining of the cell membrane or cytoplasm of tumor cells in the central and invasive front of the tumor. Samples were categorized into 3 groups based on the intensity of PD-L1 expression. CD8<sup>+</sup> lymphocytes expressing PD-1 and CD163<sup>+</sup> macrophages were used to determine the number of cell nuclei at the invasive front, similar to PD-L1. CMTM6 levels were determined and used to stratify samples into 3 groups. <b><i>Results:</i></b> PD-L1 expression was higher in the invasive front (26.2%) than in the central portion of the tumors (7.4%; <i>p</i> < 0.001). Moreover, lymphatic and vascular invasion were more frequently observed in samples with high levels of PD-L1 (lymphatic invasion: 60.7 vs. 35.4%, <i>p</i> = 0.0026, and vascular invasion: 39.3 vs. 16.5%, <i>p</i> = 0.0018). There was no correlation between PD-L1 expression and the levels of PD-1, CD8, CD163, and CMTM6. <b><i>Conclusions:</i></b> PD-L1-expressing cancer cells at the invasive front of gastric cancer influence the initial stages of tumor invasion and lymphovascular permeation in early-stage gastric cancers. Immune checkpoint signaling may be the driving force in the invasive front during the invasion of the submucosa beyond the lamina muscularis mucosa.
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Liu, Li, Yudong Wu, Cheng Zhang, Chong Zhou, Yining Li, Yi Zeng, Chunbo Zhang, et al. "Cancer-associated adipocyte-derived G-CSF promotes breast cancer malignancy via Stat3 signaling." Journal of Molecular Cell Biology 12, no. 9 (April 2, 2020): 723–37. http://dx.doi.org/10.1093/jmcb/mjaa016.
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Abstract Adipocyte is the most predominant cell type in the tumor microenvironment of breast cancer and plays a pivotal role in cancer progression, yet the underlying mechanisms and functional mediators remain elusive. We isolated primary preadipocytes from mammary fat pads of human breast cancer patients and generated mature adipocytes and cancer-associated adipocytes (CAAs) in vitro. The CAAs exhibited significantly different gene expression profiles as assessed by transcriptome sequencing. One of the highly expressed genes in CAAs is granulocyte colony-stimulating factor (G-CSF). Treatment with recombinant human G-CSF protein or stable expression of human G-CSF in triple-negative breast cancer (TNBC) cell lines enhanced epithelial–mesenchymal transition, migration, and invasion of cancer cells, by activating Stat3. Accordantly, targeting G-CSF/Stat3 signaling with G-CSF-neutralizing antibody, a chemical inhibitor, or siRNAs for Stat3 could all abrogate CAA- or G-CSF-induced migration and invasion of breast cancer cells. The pro-invasive genes MMP2 and MMP9 were identified as target genes of G-CSF in TNBC cells. Furthermore, in human breast cancer tissues, elevated G-CSF expression in adipocytes is well correlated with activated Stat3 signal in cancer cells. Together, our results suggest a novel strategy to intervene with invasive breast cancers by targeting CAA-derived G-CSF.
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Zhang, X., X. Rong, Y. Chen, and L. Su. "Methylation-mediated loss of SFRP2 enhances invasiveness of non–small cell lung cancer cells." Human & Experimental Toxicology 37, no. 2 (February 21, 2017): 155–62. http://dx.doi.org/10.1177/0960327117693071.
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The malignancy of non–small cell lung cancer (NSCLC) largely results from its invasive manner. Secreted frizzled-related proteins (SFRPs) have been recently found to suppress the invasiveness of some cancers. On the other hand, the methylation of SFRPs increases protein degradation to reduce the activity of SFRPs, resulting in increased tumor cell invasion and cancer metastasis. However, the role of SFRPs in the invasion of NSCLC has not been reported. Here we analyzed the regulation of SFRPs in NSCLC cells and its effects on cell invasion. We found that SFRP2 mRNA was significantly decreased and methylation of SFRP2 gene was significantly increased in NSCLC tissue, compared to the paired adjacent nontumor tissue. Moreover, SFRP2 expression was significantly decreased in NSCLC cell lines. In NSCLC cell lines, the SFRP2 expression would be restored by the demethylation of SFRP2 gene with 5′-aza-deoxycytidine in NSCLC cell lines, at the levels of both mRNA and protein. Thus, the cell invasion would be suppressed. Furthermore, the demethylation of SFRP2 gene appeared to inhibit Zinc Finger E-Box Binding Homeobox 1 (ZEB1) and matrix metallopeptidase 9 (MMP9), two key factors that enhance NSCLC cell invasion. Thus, SFRP2 may inhibit NSCLC invasion by suppressing ZEB1 and MMP9, while its methylation promotes NSCLC invasion.
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Sanders, Mary Ann, Laura Dominici, Christine Denison, Mehra Golshan, Tad Wiecorek, and Susan C. Lester. "Paget Disease of the Breast With Invasion From Nipple Skin Into the Dermis: An Unusual Type of Skin Invasion Not Associated With an Adverse Outcome." Archives of Pathology & Laboratory Medicine 137, no. 1 (January 1, 2013): 72–76. http://dx.doi.org/10.5858/arpa.2011-0611-oa.
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Context.—Paget disease is an uncommon skin manifestation of breast cancer, associated with either invasive carcinoma or ductal carcinoma in situ in the underlying breast. In very rare cases, tumor cells within the epidermis invade through the basement membrane of the skin into the dermis. Objectives.—To identify a series of cases of Paget disease with direct dermal invasion and to investigate the clinicopathologic features and outcome. Design.—Cases were identified during a 6-year period from the files of 2 hospitals. The clinical histories, imaging studies, and pathology reports were reviewed. Results.—Seven patients were identified, 5 with microinvasion (<0.1 cm) and 2 with 0.2- or 0.3-cm invasive carcinomas in the dermis. No lymphovascular invasion was seen. Sentinel nodes were negative in 3 patients who underwent biopsy. Five patients were treated with breast conservation with radiation. Three patients were at high risk for breast cancer because of prior breast cancer, Li-Fraumeni syndrome, or radiation for Hodgkin disease. The latter 2 patients underwent bilateral mastectomies. Three patients received hormonal therapy and 1 oophorectomy. No patient received chemotherapy. At follow-ups ranging from 4 to 66 months (median, 20 months), there have been no recurrences. Conclusions.—Patients with direct dermal invasion from Paget disease had a favorable outcome during the available follow-up period. This type of dermal involvement must be distinguished from locally advanced invasive carcinomas with skin invasion classified as T4b in the American Joint Cancer Commission staging system, as cancers with other types of skin invasion are associated with a poor prognosis.
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van de Merbel, Arjanneke F., Onno van Hooij, Geertje van der Horst, Cindy C. M. van Rijt-van de Westerlo, Maaike H. van der Mark, Henry Cheung, Jan Kroon, et al. "The Identification of Small Molecule Inhibitors That Reduce Invasion and Metastasis of Aggressive Cancers." International Journal of Molecular Sciences 22, no. 4 (February 8, 2021): 1688. http://dx.doi.org/10.3390/ijms22041688.
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Transformed epithelial cells can activate programs of epithelial plasticity and switch from a sessile, epithelial phenotype to a motile, mesenchymal phenotype. This process is linked to the acquisition of an invasive phenotype and the formation of distant metastases. The development of compounds that block the acquisition of an invasive phenotype or revert the invasive mesenchymal phenotype into a more differentiated epithelial phenotype represent a promising anticancer strategy. In a high-throughput assay based on E-cadherin (re)induction and the inhibition of tumor cell invasion, 44,475 low molecular weight (LMW) compounds were screened. The screening resulted in the identification of candidate compounds from the PROAM02 class. Selected LMW compounds activated E-cadherin promoter activity and inhibited cancer cell invasion in multiple metastatic human cancer cell lines. The intraperitoneal administration of selected LMW compounds reduced the tumor burden in human prostate and breast cancer in vivo mouse models. Moreover, selected LMW compounds decreased the intra-bone growth of xenografted human prostate cancer cells. This study describes the identification of the PROAM02 class of small molecules that can be exploited to reduce cancer cell invasion and metastases. Further clinical evaluation of selected candidate inhibitors is warranted to address their safety, bioavailability and antitumor efficacy in the management of patients with aggressive cancers.
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Schneider, Lisa, Junnan Liu, Cheng Zhang, Anca Azoitei, Sabine Meessen, Xi Zheng, Catharina Cremer, et al. "The Role of Interleukin-1-Receptor-Antagonist in Bladder Cancer Cell Migration and Invasion." International Journal of Molecular Sciences 22, no. 11 (May 30, 2021): 5875. http://dx.doi.org/10.3390/ijms22115875.
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Background: The interleukin-1-receptor antagonist IL1RA (encoded by the IL1RN gene) is a potent competitive antagonist to interleukin-1 (IL1) and thereby is mainly involved in the regulation of inflammation. Previous data indicated a role of IL1RA in muscle-invasive urothelial carcinoma of the bladder (UCB) as well as an IL1-dependent decrease in tissue barrier function, potentially contributing to cancer cell invasion. Objective: Based on these observations, here we investigated the potential roles of IL1RA, IL1A, and IL1B in bladder cancer cell invasion in vitro. Methods: Cell culture, real-time impedance sensing, invasion assays (Boyden chamber, pig bladder model), qPCR, Western blot, ELISA, gene overexpression. Results: We observed a loss of IL1RA expression in invasive, high-grade bladder cancer cell lines T24, UMUC-3, and HT1197 while IL1RA expression was readily detectable in the immortalized UROtsa cells, the non-invasive bladder cancer cell line RT4, and in benign patient urothelium. Thus, we modified the invasive human bladder cancer cell line T24 to ectopically express IL1RA, and measured changes in cell migration/invasion using the xCELLigence Real-Time-Cell-Analysis (RTCA) system and the Boyden chamber assay. The real-time observation data showed a significant decrease of cell migration and invasion in T24 cells overexpressing IL1RA (T24-IL1RA), compared to cells harboring an empty vector (T24-EV). Concurrently, tumor cytokines, e.g., IL1B, attenuated the vascular endothelial barrier, which resulted in a reduction of the Cell Index (CI), an impedance-based dimensionless unit. This reduction could be reverted by the simultaneous incubation with IL1RA. Moreover, we used an ex vivo porcine organ culture system to evaluate cell invasion capacity and showed that T24-IL1RA cells showed significantly less invasive capacity compared to parental T24 cells or T24-EV. Conclusions: Taken together, our results indicate an inverse correlation between IL1RA expression and tumor cell invasive capacity and migration, suggesting that IL1RA plays a role in bladder carcinogenesis, while the exact mechanisms by which IL1RA influences tumor cells migration/invasion remain to be clarified in future studies. Furthermore, we confirmed that real-time impedance sensing and the porcine ex vivo organ culture methods are powerful tools to discover differences in cancer cell migration and invasion.
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Thakkar, Arvind, Ahmed Aljameeli, Shibu Thomas, and Girish V. Shah. "A-kinase anchoring protein 2 is required for calcitonin-mediated invasion of cancer cells." Endocrine-Related Cancer 23, no. 1 (October 2, 2015): 1–14. http://dx.doi.org/10.1530/erc-15-0425.
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Expression of neuropeptide calcitonin (CT) and its receptor (CTR) is frequently elevated in prostate cancers (PCs) and activation of CT–CTR axis in non-invasive PC cells induces an invasive phenotype. Specific, cell-permeable inhibitors of protein kinase A abolish CTR-stimulated invasion of PC cells. Since PKA is ubiquitously distributed in cells, the present study examined the mechanism(s) by which CTR-stimulated PKA activity is regulated in time and space. CT reduced cell adhesion but increased invasion of PC cells. Both these actions were abolished by st-Ht31 inhibitory peptide suggesting the involvement of an A-kinase anchoring protein (AKAP) in CT action. Next, we identified the AKAP associated with CT action by the subtraction of potential AKAP candidates using siRNAs. Knock-down of membrane-associated AKAP2, but not other AKAPs, abolished CT-stimulated invasion. Stable knock-down of AKAP2 in PC3-CTR cells remarkably decreased their cell proliferation, invasion, clonogenicity and ability to form orthotopic tumors and distant metastases in nude mice. Re-expression of AKAP2-wt restored these characteristics. Primary PC specimens displayed remarkable upregulation of CTR/AKAP2 expression as compared to benign prostates. Metastatic cancers displayed significantly higher CTR/AKAP2 expression than localized cancers. These results for the first time demonstrate that AKAP2 is expressed in human prostates, its expression is elevated in metastatic prostate cancer, and the knock-down of its expression remarkably decreased tumorigenicity and metastatic ability of prostate cancer cells. AKAP2 may serve as a critical component of CTR-mediated oncogenic actions.
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Dankner, Matthew, Maxime Caron, Tariq Al-Saadi, WenQing Yu, Véronique Ouellet, Rima Ezzeddine, Sarah M. Maritan, et al. "Invasive growth associated with cold-inducible RNA-binding protein expression drives recurrence of surgically resected brain metastases." Neuro-Oncology 23, no. 9 (January 12, 2021): 1470–80. http://dx.doi.org/10.1093/neuonc/noab002.
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Abstract Background Sixty percent of surgically resected brain metastases (BrM) recur within 1 year. These recurrences have long been thought to result from the dispersion of cancer cells during surgery. We tested the alternative hypothesis that invasion of cancer cells into the adjacent brain plays a significant role in local recurrence and shortened overall survival. Methods We determined the invasion pattern of 164 surgically resected BrM and correlated with local recurrence and overall survival. We performed single-cell RNA sequencing (scRNAseq) of >15,000 cells from BrM and adjacent brain tissue. Validation of targets was performed with a novel cohort of BrM patient-derived xenografts (PDX) and patient tissues. Results We demonstrate that invasion of metastatic cancer cells into the adjacent brain is associated with local recurrence and shortened overall survival. scRNAseq of paired tumor and adjacent brain samples confirmed the existence of invasive cancer cells in the tumor-adjacent brain. Analysis of these cells identified cold-inducible RNA-binding protein (CIRBP) overexpression in invasive cancer cells compared to cancer cells located within the metastases. Applying PDX models that recapitulate the invasion pattern observed in patients, we show that CIRBP is overexpressed in highly invasive BrM and is required for efficient invasive growth in the brain. Conclusions These data demonstrate peritumoral invasion as a driver of treatment failure in BrM that is functionally mediated by CIRBP. These findings improve our understanding of the biology underlying postoperative treatment failure and lay the groundwork for rational clinical trial development based upon invasion pattern in surgically resected BrM.
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Mo, Yijun, Lina Lin, Jianhua Zhang, and Changhui Yu. "SOAT1 enhances lung cancer invasiveness by stimulating AKT-mediated mitochondrial fragmentation." Biochemistry and Cell Biology 100, no. 1 (February 2022): 68–74. http://dx.doi.org/10.1139/bcb-2021-0175.
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Sterol O-acyltransferase 1 (SOAT1) is a key enzyme in lipid metabolism, which mediates cholesterol esterification metabolism and is closely associated with many cancers. However, the role of SOAT1 in lung cancer invasion remains unclear. We found that SOAT1 expression was positively correlated with lung cancer invasion. Downregulation of SOAT1 inhibited invasion, mitochondrial fragmentation, AKT phosphorylation, and phospho-Drp (Ser616) in lung cancer cells and promoted intracellular free cholesterol accumulation. Mechanistically, the AKT phosphorylation inhibitor MK-2206 alleviated both SOAT1 overexpression and high expression-induced mitochondrial fragmentation and lung cancer cell invasion. Furthermore, intracellular free cholesterol accumulation reduced AKT phosphorylation, SREBP1 mRNA expression, cell invasion, and mitochondrial fragmentation in lung cancer cells with high SOAT1 expression. In summary, our findings suggest that SOAT1 promotes lung cancer invasion by activating the PI3K/AKT signaling pathway by downregulating intracellular free cholesterol levels, thereby affecting the regulation of mitochondrial fragmentation.
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Sahu, Divya, Donna E. Hansel, Richard Klemke, and Gerry Boss. "Role of mTORC2 and nitric oxide in bladder cancer invasion." Journal of Clinical Oncology 36, no. 6_suppl (February 20, 2018): 504. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.504.
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504 Background: In the United States, bladder cancer is the fourth most common cancer, with an estimated 79,000 new diagnoses and 17,000 deaths in 2017, and the eleventh most common cancer worldwide. The key driver of bladder cancer stage progression is tumor cell invasion which has limited response to current chemotherapy options and hence, newer therapies directed against invasion are key to improving the treatment of bladder cancer. Our laboratory has identified mammalian target of rapamycin complex 2 (mTORC2) as a driver of bladder cancer cell invasion. We have also recently shown that arginine, the nitric oxide (NO) precursor, is implicated in bladder cancer progression. We evaluated the interaction between these two pathways to promote invasion. Methods: Expression of inducible and endothelial nitric oxide synthases (iNOS and eNOS) in FFPE tissue sections of progressive disease was assessed by IHC and correlated with histopathology, progression and stage based on moderate to strong expression (2+, 3+) compared to absent to weak expression (0, 1+).We utilized gene silencing methods and NOS inhibitors and NO scavenger for effects on bladder cancer invasion and migration. We assessed mTORC2 pathway activity and NOS levels in invasive cell tip protrusions called “invadopodia” and evaluated if mTORC2 regulates NOS localization and/or activity. We used a novel zebrafish model to characterize the effects of mTORC2 and NO on bladder cancer metastases. Results: We found that eNOS and iNOS are elevated in invasive human bladder tumors and cell lines and their ablation reduces bladder cancer cell migration and invasion. mTORC2 silencing can affect levels of iNOS and eNOS in bladder cancer cell lines. Silencing of mTORC2, eNOS or iNOS reduced metastases of bladder cancer cells within zebrafish. Conclusions: mTORC2 pathway is a key driver of bladder cancer invasion and metastases by regulating the NO pathway and both mTORC2 and NO can be targets for bladder cancer therapy, which would benefit patient outcomes.
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Schuster, Anne, Virginie Neirinckx, Eliane Klein, Petr V. Nazarov, Anais Oudin, Arnaud Muller, Fransisco Azuaje, Christel Herold-Mende, Barbara Klink, and Simone Niclou. "ANGI-02. GENOME-WIDE shRNA SCREEN IDENTIFIES CANDIDATE GENES DRIVING GLIOBLASTOMA INVASION." Neuro-Oncology 21, Supplement_6 (November 2019): vi30. http://dx.doi.org/10.1093/neuonc/noz175.113.
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Abstract BACKGROUND A major hallmark of glioblastoma (GBM) is its invasive capacity, contributing to its aggressive behaviour. Invasive cells cannot be easily removed by surgery or irradiation and eventually result in lethal recurrence. A better understanding of the invasion process and the key molecular players underlying the invasive potential of GBM may lead to the identification of new therapeutic targets for GBM patients. MATERIAL AND METHODS To identify candidate genes responsible for invasion, a genome-wide shRNA screen was performed in patient-derived GBM cultures. The most promising candidate was validated in in vitro invasion assays, ex vivo brain slice cultures and in vivo orthotopic xenografts in mice. Gene knockdown in invasive GBM cells was compared with overexpression in non-invasive cells. RNAseq of knockdown cells, along with the generation of deletion constructs were applied to uncover the mechanisms regulating invasion. RESULTS A zinc-finger domain containing protein was identified as an invasion essential candidate gene. Knockdown of this gene confirmed a strong impact on invasion in highly invasive GBM cells. In contrast, gene overexpression switched non-invasive GBM cells to an invasive phenotype. Deletion of one or both zinc-finger motifs decreased invasion indicating that both are essential for regulating invasion. Mutation of the nuclear localisation signal resulted in retention of the protein in the cytoplasm and loss of the invasion phenotype demonstrating that the protein activity is required in the nucleus. Gene expression analyses revealed that invasion-related genes are significantly regulated by the candidate gene once it is localized in the nucleus. CONCLUSION We identified a zinc-finger containing protein as a novel driver of GBM invasion, presumably through transcription factor activity resulting in the induction of an invasive transcriptional program. This protein and its downstream pathway may represent novel promising targets to overcome invasive capacities in GBM.
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Pueblitz, Siegfried. "Invasion in Lung Cancer." American Journal of Surgical Pathology 13, no. 12 (December 1989): 1071. http://dx.doi.org/10.1097/00000478-198912000-00013.
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Ferrarelli, L. K. "Centrosomes Coordinate Cancer Invasion." Science Signaling 7, no. 329 (June 10, 2014): ec156-ec156. http://dx.doi.org/10.1126/scisignal.2005581.
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Häger, Anna, Stephanie Alexander, and Peter Friedl. "Cancer invasion and resistance." European Journal of Cancer Supplements 11, no. 2 (September 2013): 291–93. http://dx.doi.org/10.1016/j.ejcsup.2013.07.055.
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Kim, Young S., Lance A. Liotta, and Elise C. Kohn. "Cancer Invasion and Metastasis." Hospital Practice 28, no. 5 (May 15, 1993): 92–96. http://dx.doi.org/10.1080/21548331.1993.11442792.
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Wittekind, Christian, and Matthias Neid. "Cancer Invasion and Metastasis." Oncology 69, no. 1 (2005): 14–16. http://dx.doi.org/10.1159/000086626.
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Liebig, Catherine, Gustavo Ayala, Jonathan A. Wilks, David H. Berger, and Daniel Albo. "Perineural invasion in cancer." Cancer 115, no. 15 (August 1, 2009): 3379–91. http://dx.doi.org/10.1002/cncr.24396.
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Liotta, L. A. "Cancer invasion and metastases." JAMA: The Journal of the American Medical Association 263, no. 8 (February 23, 1990): 1123–26. http://dx.doi.org/10.1001/jama.263.8.1123.
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Liotta, Lance A. "Cancer Invasion and Metastases." JAMA: The Journal of the American Medical Association 263, no. 8 (February 23, 1990): 1123. http://dx.doi.org/10.1001/jama.1990.03440080101032.
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Jimenez, Lizandra, Sangeeta K. Jayakar, Thomas J. Ow, and Jeffrey E. Segall. "Mechanisms of Invasion in Head and Neck Cancer." Archives of Pathology & Laboratory Medicine 139, no. 11 (June 5, 2015): 1334–48. http://dx.doi.org/10.5858/arpa.2014-0498-ra.
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Context The highly invasive properties demonstrated by head and neck squamous cell carcinoma (HNSCC) are often associated with locoregional recurrence and lymph node metastasis in patients and is a key factor leading to an expected 5-year survival rate of approximately 50% for patients with advanced disease. It is important to understand the features and mediators of HNSCC invasion so that new treatment approaches can be developed. Objectives To provide an overview of the characteristics, mediators, and mechanisms of HNSCC invasion. Data Sources A literature review of peer-reviewed articles in PubMed on HNSCC invasion. Conclusions Histologic features of HNSCC tumors can help predict prognosis and influence clinical treatment decisions. Cell surface receptors, signaling pathways, proteases, invadopodia function, epithelial-mesenchymal transition, microRNAs, and tumor microenvironment are all involved in the regulation of the invasive behavior of HNSCC cells. Identifying effective HNSCC invasion inhibitors has the potential to improve outcomes for patients by reducing the rate of spread and increasing responsiveness to chemoradiation.
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Bilandzic, Maree, Adam Rainczuk, Emma Green, Nicole Fairweather, Thomas W. Jobling, Magdalena Plebanski, and Andrew N. Stephens. "Keratin-14 (KRT14) Positive Leader Cells Mediate Mesothelial Clearance and Invasion by Ovarian Cancer Cells." Cancers 11, no. 9 (August 22, 2019): 1228. http://dx.doi.org/10.3390/cancers11091228.
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Epithelial ovarian cancer metastasis is driven by spheroids, which are heterogeneous cancer cell aggregates released from the primary tumour mass that passively disseminate throughout the peritoneal cavity to promote tumour spread, disease recurrence, and acquired chemoresistance. Despite their clinical importance, the molecular events that control spheroid attachment and invasion into underlying healthy tissues remain poorly understood. We examined a novel in vitro invasion model using imaging mass spectrometry to establish a “snapshot” of the spheroid/mesothelial interface. Amongst numerous adhesion-related proteins, we identified a sub-population of highly motile, invasive cells that expressed the basal epithelial marker KRT14 as an absolute determinant of invasive potential. The loss of KRT14 completely abrogated the invasive capacity, but had no impact on cell viability or proliferation, suggesting an invasion-specific role. Our data demonstrate KRT14 cells as an ovarian cancer “leader cell” phenotype underlying tumor invasion, and suggest their importance as a clinically relevant target in directed anti-tumour therapies.
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Rojo, Daniel, Alejandro Madrid, Sebastián San Martín, Mario Párraga, Maria Aparecida Silva Pinhal, Joan Villena, and Manuel Valenzuela-Valderrama. "Resveratrol Decreases the Invasion Potential of Gastric Cancer Cells." Molecules 27, no. 10 (May 10, 2022): 3047. http://dx.doi.org/10.3390/molecules27103047.
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The cancer-preventive agent Resveratrol (RSV) [3,5,4′-trihydroxytrans-stilbene] is a widely recognized antioxidant molecule with antitumoral potential against several types of cancers, including prostate, hepatic, breast, skin, colorectal, and pancreatic. Herein, we studied the effect of RSV on the cell viability and invasion potential of gastric cancer cells. AGS and MKN45 cells were treated with different doses of RSV (0–200 μM) for 24 h. Cell viability was determined using the Sulphorhodamine B dye (SRB) assay. For invasion assays, gastric cells were pre-treated with RSV (5–25 μM) for 24 h and then seeded in a Transwell chamber with coating Matrigel. The results obtained showed that RSV inhibited invasion potential in both cell lines. Moreover, to elucidate the mechanism implicated in this process, we analyzed the effects of RSV on SOD, heparanase, and NF-κB transcriptional activity. The results indicated that RSV increased SOD activity in a dose-dependent manner. Conversely, RSV significantly reduced the DNA-binding activity of NF-κB and the enzymatic activity of heparanase in similar conditions, which was determined using ELISA-like assays. In summary, these results show that RSV increases SOD activity but decreases NF-kB transcriptional activity and heparanase enzymatic activity, which correlates with the attenuation of invasion potential in gastric cancer cells. To our knowledge, no previous study has described the effect of RSV on heparanase activity. This article proposes that heparanase could be a key effector in the invasive events occurring during gastric cancer metastasis.
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Chrisafis, George, Tianhong Wang, Konstadinos Moissoglu, Alexander N. Gasparski, Yeap Ng, Roberto Weigert, Stephen J. Lockett, and Stavroula Mili. "Collective cancer cell invasion requires RNA accumulation at the invasive front." Proceedings of the National Academy of Sciences 117, no. 44 (October 15, 2020): 27423–34. http://dx.doi.org/10.1073/pnas.2010872117.
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Localization of RNAs at protrusive regions of cells is important for single-cell migration on two-dimensional surfaces. Protrusion-enriched RNAs encode factors linked to cancer progression, such as the RAB13 GTPase and the NET1 guanine nucleotide exchange factor, and are regulated by the tumor-suppressor protein APC. However, tumor cells in vivo often do not move as single cells but rather utilize collective modes of invasion and dissemination. Here, we developed an inducible system of three-dimensional (3D) collective invasion to study the behavior and importance of protrusion-enriched RNAs. We find that, strikingly, both theRAB13andNET1RNAs are enriched specifically at the invasive front of leader cells in invasive cell strands. This localization requires microtubules and coincides with sites of high laminin concentration. Indeed, laminin association and integrin engagement are required for RNA accumulation at the invasive front. Importantly, perturbing RNA accumulation reduces collective 3D invasion. Examination of in vivo tumors reveals a similar localization of theRAB13andNET1RNAs at potential invasive sites, suggesting that this mechanism could provide a targeting opportunity for interfering with collective cancer cell invasion.
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Hau, Andrew M., Andrew Gilder, Jing-jing Hu, Steven L. Gonias, and Donna E. Hansel. "uPAR and mTORC2 as coupled targets for therapeutics development in bladder cancer." Journal of Clinical Oncology 34, no. 2_suppl (January 10, 2016): 447. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.447.
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447 Background: Bladder cancer currently ranks as the fifth most common and the single most expensive cancer to manage in the United States. Although it is established that invasive behavior is a major predictor of diminished outcomes for patients with bladder cancer, the molecular mechanisms governing bladder cancer cell invasion are not well understood. The urokinase receptor (uPAR) and mammalian target of rapamycin complex 2 (mTORC2) represent two powerful pro-invasion candidates that have increased expression in high-grade, invasive bladder cancer, though the former has not been characterized in detail in bladder cancer. Therefore, the aims of this study are to characterize the uPAR signaling network and delineate the signaling interplay between mTORC2 and uPAR in bladder cancer. Methods: Using immunoblot and RT-qPCR analyses, we evaluated uPAR expression in a panel of immortalized bladder cancer cell lines: UROtsa, RT4, UMUC3, T24 and J82. uPAR influence on mTORC1 and mTORC2 signaling was determined by immunoblot analysis following targeted gene-silencing of uPAR using siRNA. Additionally, the effects of uPAR knockdown on cell migration and invasion were investigated using modified scratch-wound migration and transwell invasion assays. Lastly, signaling interplay between uPAR and mTORC2 was investigated by evaluating the effects of uPAR and mTORC2 silencing on Rac1 activity. Results: uPAR knockdown in a subset (T24 and J82) of invasive bladder cancer cell lines inhibited mTORC2, but not mTORC1, activity as measured by P-AKT S473 and P-S6 levels. We found that uPAR silencing in T24 and J82 cells resulted in significant reductions in cell migration and invasion through Matrigel. This is likely attributed to inhibition of Rac1 and decreased lamellipodia formation. Conclusions: Collectively, our results identify uPAR and mTORC2 as major regulators of bladder cancer cell invasion and that these two systems are linked through Rac1. Further investigation of uPAR and mTORC2 inhibition using uPAR-targeting antibodies and mTOR inhibitors in an in vivo mouse model of bladder cancer will determine if these signaling pathways are therapeutically beneficial for the treatment of bladder cancer.
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Hong, Keun-Seok, Hyemin Kim, Seon-Hee Kim, Minju Kim, and Jiyun Yoo. "Calponin 3 Regulates Cell Invasion and Doxorubicin Resistance in Gastric Cancer." Gastroenterology Research and Practice 2019 (February 18, 2019): 1–7. http://dx.doi.org/10.1155/2019/3024970.
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Calponin 3 (CNN3) is an F-actin-binding protein that regulates actin cytoskeletal rearrangement. However, the role of CNN3 in cancer cell invasion and resistance to chemotherapeutic agents has not yet been investigated. The present study was undertaken to investigate whether CNN3 influences cancer-related phenotypes in gastric cancer. We demonstrate that CNN3 contributes to cell invasion and resistance to doxorubicin in gastric cancer. CNN3 expression was markedly elevated in highly invasive cancer cell lines compared to less invasive or noninvasive cancer cell lines. Depletion of CNN3 protein suppressed the invasive ability of gastric cancer cells. The highly invasive MKN-28 gastric cancer cells were more resistant to doxorubicin than the noninvasive MKN-45 cells; however, knockdown of CNN3 expression in MKN-28 cells resensitized them to doxorubicin treatment. Taken together, our results suggest that CNN3 plays a key role in invasiveness and doxorubicin resistance in gastric cancer cells.
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Schuster, A., V. Neirinckx, E. Klein, P. V. Nazarov, A. Oudin, A. Muller, F. Azuaje, C. Herold-Mende, B. Klink, and S. P. Niclou. "P11.26 Genome-wide shRNA screen identifies candidate genes driving glioblastoma invasion." Neuro-Oncology 21, Supplement_3 (August 2019): iii48. http://dx.doi.org/10.1093/neuonc/noz126.172.
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Abstract BACKGROUND A major hallmark of glioblastoma (GBM) is its highly invasive capacity, contributing to its aggressive behaviour. Since invasive cells cannot be easily removed by surgery or irradiation, they are left behind and eventually result in lethal recurrence. Therefore, a better understanding of the invasion process and of the key molecular players underlying the invasive capacities of GBM may lead to the identification of new therapeutic targets for GBM patients. MATERIAL AND METHODS To identify candidate genes responsible for invasion, a genome-wide shRNA screen was performed in patient-derived GBM sphere cultures. The phenotype of the most promising candidate was validated in in vitro invasion assays, ex vivo brain slice cultures and in vivo orthotopic xenografts in mice. Gene knockdown in invasive GBM cell lines was compared with overexpression in non-invasive cells. RNA sequencing of knockdown cells, along with the generation of deletion constructs were applied to uncover the mechanisms regulating invasion. RESULTS Through a whole genome shRNA screen, a zinc-finger containing protein was identified as an invasion essential candidate gene. Knockdown of this gene confirmed a strong decrease in invasion capacity in two highly invasive GBM cell lines. In contrast, gene overexpression switched non-invasive GBM cells to an invasive phenotype. Deletion of either one or both zinc-finger motifs led to decreased invasion indicating that the two zinc-finger motifs are essential for regulating invasion. Mutation of the nuclear localisation signal resulted in retention of the protein in the cytoplasm and loss of the invasion phenotype demonstrating that the protein activity is required in the nucleus. Gene expression analyses revealed that invasion-related genes are significantly regulated by the candidate gene once it is localized in the nucleus. CONCLUSION We identified a zinc-finger containing protein as a novel driver of GBM invasion, presumably through a transcription factor activity resulting in the induction of an invasive transcriptional program. This protein and its downstream pathway may represent a novel promising target to overcome invasive capacities in GBM.
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Chang, Julie, and Ovijit Chaudhuri. "Beyond proteases: Basement membrane mechanics and cancer invasion." Journal of Cell Biology 218, no. 8 (July 17, 2019): 2456–69. http://dx.doi.org/10.1083/jcb.201903066.
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In epithelial cancers, cells must invade through basement membranes (BMs) to metastasize. The BM, a thin layer of extracellular matrix underlying epithelial and endothelial tissues, is primarily composed of laminin and collagen IV and serves as a structural barrier to cancer cell invasion, intravasation, and extravasation. BM invasion has been thought to require protease degradation since cells, which are typically on the order of 10 µm in size, are too large to squeeze through the nanometer-scale pores of the BM. However, recent studies point toward a more complex picture, with physical forces generated by cancer cells facilitating protease-independent BM invasion. Moreover, collective cell interactions, proliferation, cancer-associated fibroblasts, myoepithelial cells, and immune cells are all implicated in regulating BM invasion through physical forces. A comprehensive understanding of BM structure and mechanics and diverse modes of BM invasion may yield new strategies for blocking cancer progression and metastasis.
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Makboul, Marwa, Shimaa Farghaly, and Islam F. Abdelkawi. "Multiparametric MRI in differentiation between muscle invasive and non-muscle invasive urinary bladder cancer with vesical imaging reporting and data system (VI-RADS) application." British Journal of Radiology 92, no. 1104 (December 2019): 20190401. http://dx.doi.org/10.1259/bjr.20190401.
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Objective: To evaluate role of multiparametric MRI (mp-MRI) in differentiation between invasive and non-invasive bladder cancer and accuracy of vesical imaging reporting and data system (VI-RADS) score. Methods and materials: 50 patients diagnosed as cancer bladder were enrolled in this study, mp-MRI including conventional (T1 weighted imaging and high resolution T2 weighted imaging) and functional sequences (diffusion-weighted imaging and dynamic contrast enhanced-MRI) were done, all data were regrouped to evaluate the accuracy of each separate sequence and mp-MRI in distinguishing non-muscle invasive from muscle-invasive tumors, with VI-RADS score application and comparison with pathological findings, then interobserver agreement for detection of muscle invasion according to mp-MRI and VI-RADS scoring system findings was calculated. Results: Diagnostic accuracy of mp-MRI in differentiation between muscle invasive and non-muscle invasive bladder cancer was (84%) with highest sensitivity (78%), very good agreement between mp-MRI and histopathological data (k = 0.87), and highest area under curve (AUC) reaching 0.83, dynamic contrast enhanced-MRI sequence showed the highest accuracy in muscle invasion detection by (88%), with highest AUC 0.83. Diagnostic accuracy of VI-RADS score in detection of muscle invasion was 84%, with specificity and negative predictive value of 88% and AUC was 0.83. Interobserver agreement was strong as regard diagnostic performance of mp-MRI and VI-RADS scoring for detection of muscle invasion reaching (K = 0.82, p < 0.001) and (K = 0.87, p < 0.001) respectively. Conclusion: mp-MRI is considered as comprehensive and effective tool for determination of muscle invasion in cases of urinary bladder cancer. Also VI-RADS scoring system can accurately differentiate between invasive and non-invasive bladder cancer. Advances in knowledge: The VI-RADS system was recently suggested for the uniform evaluation of muscle invasion in cancer bladder by mp-MRI. In this paper, we applied this system to 50 cases to evaluate its ease and compared the results with the histopathological findings for evaluation of its accuracy.
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Hira, Vashendriya VV, Barbara Breznik, Cornelis JF Van Noorden, Tamara Lah, and Remco J. Molenaar. "2D and 3D in vitro assays to quantify the invasive behavior of glioblastoma stem cells in response to SDF-1α." BioTechniques 69, no. 5 (November 2020): 339–46. http://dx.doi.org/10.2144/btn-2020-0046.
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Invasion is a hallmark of cancer and therefore in vitro invasion assays are important tools in cancer research. We aimed to describe in vitro 2D transwell assays and 3D spheroid assays to quantitatively determine the invasive behavior of glioblastoma stem cells in response to the chemoattractant SDF-1α. Matrigel was used as a matrix in both assays. We demonstrated quantitatively that SDF-1α increased invasive behavior of glioblastoma stem cells in both assays. We conclude that the 2D transwell invasion assay is easy to perform, fast and less complex whereas the more time-consuming 3D spheroid invasion assay is physiologically closer to the in vivo situation.
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Palmbos, Phillip Lee, Lidong Wang, Huibin Yang, Taylor Detzler, Gina Ney, Yair Lotan, Patrick N. Healy, et al. "Novel oncogenic function of ATDC in bladder cancer." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 4591. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.4591.
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4591 Background: Bladder cancer is a common and deadly disease, but the molecular events leading to its initiation and progression are incompletely understood. We recently identified Ataxia-Telangiectasia Group D Associated (ATDC) as a novel oncogene which drives tumor proliferation and invasion in pancreatic carcinoma (Cancer Cell, 2009). In this study, we describe the role of ATDC as an oncogene in bladder cancer. Methods: To further determine the oncogenic role of ATDC, we generated ATDC transgenic (tg) mice in which ATDC expression was driven by a CMV promoter and characterized the resulting tumors. Results: Interestingly, the dominant phenotype in these mice was the development of both non-invasive and invasive urothelial carcinomas (9% and 20% respectively, average age of onset 10-12 months of age). Histologically, these tumors were indistinguishable from human urothelial carcinomas. Gene expression profiling of invasive tumors derived from ATDC tg mice demonstrated a marked overlap with gene signatures of human invasive bladder cancers. ATDC was the 11th most highly up-regulated gene in bladder cancers represented in the Oncomine gene expression database. Analysis of a human bladder cancer tissue microarray (311 samples) by IHC showed elevated expression in 70% (173/252) of muscle-invasive carcinomas, 22% (5/23) of papillary tumors and little or no expression in normal bladder urothelium. ATDC tg mouse bladder tumors demonstrated loss of p53 signaling and down-regulation of PTEN expression, which correlated with ATDC induced methylation of the PTEN promoter by DNMT3A. Furthermore, ATDC knock-down in invasive cancer cell lines resulted in decreased proliferation, invasion and reactivation of p53-mediated signaling and PTEN expression. Conclusions: ATDC is a novel oncogene that is highly expressed in human bladder cancers and is sufficient to drive the development of invasive bladder tumors in tg mice. The mechanism by which ATDC drives bladder cancer formation involves alterations in p53 and PTEN pathways known to be important in bladder tumorigenesis.
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Ndoye, Abibatou, Rakshitha Pandulal Miskin, and C. Michael DiPersio. "Integrin α3β1 Represses Reelin Expression in Breast Cancer Cells to Promote Invasion." Cancers 13, no. 2 (January 19, 2021): 344. http://dx.doi.org/10.3390/cancers13020344.
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Integrin α3β1, a cell adhesion receptor for certain laminins, is known to promote breast tumor growth and invasion. Our previous gene microarray study showed that the RELN gene, which encodes the extracellular glycoprotein Reelin, was upregulated in α3β1-deficient (i.e., α3 knockdown) MDA-MB-231 cells. In breast cancer, reduced RELN expression is associated with increased invasion and poor prognosis. In this study we demonstrate that α3β1 represses RELN expression to enhance breast cancer cell invasion. RELN mRNA was significantly increased upon RNAi-mediated α3 knockdown in two triple-negative breast cancer cell lines, MDA-MB-231 and SUM159. Modulation of baseline Reelin levels altered invasive potential, where enhanced Reelin expression in MDA-MB-231 cells reduced invasion, while RNAi-mediated suppression of Reelin in SUM159 cells increased invasion. Moreover, treatment of α3β1-expressing MDA-MB-231 cells with culture medium that was conditioned by α3 knockdown MDA-MB-231 cells led to decreased invasion. RNAi-mediated suppression of Reelin in α3 knockdown MDA-MB-231 cells mitigated this effect of conditioned-medium, identifying secreted Reelin as an inhibitor of cell invasion. These results demonstrate a novel role for α3β1 in repressing Reelin in breast cancer cells to promote invasion, supporting this integrin as a potential therapeutic target.
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Moffitt, Laura, Nazanin Karimnia, Andrew Stephens, and Maree Bilandzic. "Therapeutic Targeting of Collective Invasion in Ovarian Cancer." International Journal of Molecular Sciences 20, no. 6 (March 22, 2019): 1466. http://dx.doi.org/10.3390/ijms20061466.
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Ovarian cancer is the seventh most commonly diagnosed cancer amongst women and has the highest mortality rate of all gynaecological malignancies. It is a heterogeneous disease attributed to one of three cell types found within the reproductive milieu: epithelial, stromal, and germ cell. Each histotype differs in etiology, pathogenesis, molecular biology, risk factors, and prognosis. Furthermore, the origin of ovarian cancer remains unclear, with ovarian involvement secondary to the contribution of other gynaecological tissues. Despite these complexities, the disease is often treated as a single entity, resulting in minimal improvement to survival rates since the introduction of platinum-based chemotherapy over 30 years ago. Despite concerted research efforts, ovarian cancer remains one of the most difficult cancers to detect and treat, which is in part due to the unique mode of its dissemination. Ovarian cancers tend to invade locally to neighbouring tissues by direct extension from the primary tumour, and passively to pelvic and distal organs within the peritoneal fluid or ascites as multicellular spheroids. Once at their target tissue, ovarian cancers, like most epithelial cancers including colorectal, melanoma, and breast, tend to invade as a cohesive unit in a process termed collective invasion, driven by specialized cells termed “leader cells”. Emerging evidence implicates leader cells as essential drivers of collective invasion and metastasis, identifying collective invasion and leader cells as a viable target for the management of metastatic disease. However, the development of targeted therapies specifically against this process and this subset of cells is lacking. Here, we review our understanding of metastasis, collective invasion, and the role of leader cells in ovarian cancer. We will discuss emerging research into the development of novel therapies targeting collective invasion and the leader cell population.
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ALKANLI, Nevra, and Arzu Ay. "Matrix Metalloproteinase Gene Variations And Expression Levels In Breast Cancer Development." Gevher Nesibe Journal IESDR 7, no. 16 (January 25, 2022): 82–91. http://dx.doi.org/10.46648/gnj.322.
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Breast cancer is a heterogeneous disease and represents approximately 30% of all cancers in women. This type of cancer is one of the main causes of cancer-related deaths and is characterized by proliferation and metastasis of transformed cells. Extracellular matrix plays an important role in the growth, progression, prognosis, invasion and metastasis of breast cancer cells. Extracellular matrix degradation occurs by matrix metalloproteinases (MMPs) in invasive and metastatic breast cancers. MMPs are important proteolytic enzymes and are effective in tumor growth, invasion and metastasis. Various genetic variations have been identified in MMP genes and these genetic variations have been associated with changes in MMP enzyme activities, promoter activity, cell proliferation, and transcriptional regulation. Therefore, cell proliferation and tumor migration can be affected in breast cancer. Single nucleotide gene variations such as MMP-1, MMP-2, MMP-3, MMP-7, MMP-9 and MMP-12 have been associated with susceptibility to various cancer types such as breast cancer. The aim of this review is to provide general information about the pathogenesis of breast cancer as well as to examine the roles of MMP gene variations and expression levels in the development of breast cancer.
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Aleskandarany, Mohammed A., Sultan N. Sonbul, Abhik Mukherjee, and Emad A. Rakha. "Molecular Mechanisms Underlying Lymphovascular Invasion in Invasive Breast Cancer." Pathobiology 82, no. 3-4 (August 31, 2015): 113–23. http://dx.doi.org/10.1159/000433583.
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Lefebvre, Austin E. Y. T., Freddie A. Adame, and Michelle A. Digman. "A Non-Invasive Metabolic Investigation of Breast Cancer Invasion." Biophysical Journal 116, no. 3 (February 2019): 550a. http://dx.doi.org/10.1016/j.bpj.2018.11.2957.
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Kotula, Leszek, Anita Hryniewicz-Jankowska, Xiang Li, Katarzyna Augoff, Csaba Papp, Disharee Das, Sonia H. Y. Kung, et al. "Correlation of ABI1 and PTEN expression during prostate tumor progression." Journal of Clinical Oncology 40, no. 6_suppl (February 20, 2022): 172. http://dx.doi.org/10.1200/jco.2022.40.6_suppl.172.
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172 Background: Mechanisms of tumor invasion are not well defined. PTEN, a key tumor suppressor frequently inactivated in epithelial cancers, acts as a central node that controls tumor invasion. Despite PI-3 kinase-phospho-Akt pathway activation resulting in enhanced tumor growth, prostate tumors with PTEN loss undergo p53-mediated senescence that restricts tumor invasion. Methods: ABI1 downregulation is associated with epithelial-mesenchymal transition in highly invasive prostate tumors; these tumors frequently loose PTEN; therefore we set to examine genetic interaction of ABI1 and PTEN using novel mouse model of prostate cancer. We analyzed the correlation of ABI1 and PTEN expression in human PCa tumor tissue. Results: Here, using Abi1/Pten KO mouse model we identified a novel mechanism that guards tumor invasion. In Pten-null tumors upregulation of Abi1 leads to sequestration of activated Src kinase. In the absence of Abi1, this regulation is lost leading to activation of non-canonical WNT-SRC-STAT3 axis and enhanced invasion through activation of MMP2 activity. This molecular mechanism explains progression of tumors with Pten loss from PIN to invasive carcinoma upon concomitant Abi1 inactivation. In human tumors with low Abi1 and Pten are associated with aggressive phenotype, biochemical recurrence and metastasis. Conclusions: ABI1 acts as failsafe mechanism in PTEN null tumors by restricting SRC-mediated tumor invasion. ABI1 might have a predictive value in clinical setting in context of PTEN levels.
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Yamaguchi, Hideki, Shuhei Yoshida, Emi Muroi, Nachi Yoshida, Masahiro Kawamura, Zen Kouchi, Yoshikazu Nakamura, Ryuichi Sakai, and Kiyoko Fukami. "Phosphoinositide 3-kinase signaling pathway mediated by p110α regulates invadopodia formation." Journal of Cell Biology 193, no. 7 (June 27, 2011): 1275–88. http://dx.doi.org/10.1083/jcb.201009126.
Full textAbstract:
Invadopodia are extracellular matrix–degrading protrusions formed by invasive cancer cells that are thought to function in cancer invasion. Although many invadopodia components have been identified, signaling pathways that link extracellular stimuli to invadopodia formation remain largely unknown. We investigate the role of phosphoinositide 3-kinase (PI3K) signaling during invadopodia formation. We find that in human breast cancer cells, both invadopodia formation and degradation of a gelatin matrix were blocked by treatment with PI3K inhibitors or sequestration of D-3 phosphoinositides. Functional analyses revealed that among the PI3K family proteins, the class I PI3K catalytic subunit p110α, a frequently mutated gene product in human cancers, was selectively involved in invadopodia formation. The expression of p110α with cancerous mutations promoted invadopodia-mediated invasive activity. Furthermore, knockdown or inhibition of PDK1 and Akt, downstream effectors of PI3K signaling, suppressed invadopodia formation induced by p110α mutants. These data suggest that PI3K signaling via p110α regulates invadopodia-mediated invasion of breast cancer cells.