scholarly journals scribble abrogation induces tumor growth through JNK-Wnt pathways depending on cellular-microenvironment in Drosophila wing imaginal tissue

2019 ◽  
Author(s):  
Amarish Kumar Yadav ◽  
Roshan Fatima ◽  
Saripella Srikrishna
Keyword(s):  
Tumor Growth ◽  
Actin Cytoskeleton ◽  
Tumor Progression ◽  
Cell Polarity ◽  
Cancer Progression ◽  
Wing Disc ◽  
Cellular Microenvironment ◽  
Large Area ◽  
Wnt Pathways ◽  
Cytoskeleton Disruption

Abstractscribble (scrib) is a cell-polarity determinant in Drosophila and human. Cell polarity plays a crucial role in the maintenance of tissue homeostasis and its disruption leads to neoplastic cancer progression. However, the underlying mechanisms by which loss of cell-polarity regulators drives cancer progression are poorly known. In this study, we have explored the tumor progression mechanisms upon scrib knockdown in Drosophila wing imaginal disc using UASRNAi-GAL4 approach. We have found that scrib knockdown in wing disc leads to tumor growth with disrupted actin cytoskeleton, loss of cell-polarity and elevated JNK signalling, resulting in absolute early pupal lethality. Further, scrib abrogated cells in a large area of the disc are capable of invading the surrounding wild type cells and inducing apoptosis along with compensatory proliferation through JNK-Wnt pathways. Moreover, JNK pathway upstream candidate hep (JNKK) knockdown in scrib abrogated cells rescues the cell polarity defects, actin cytoskeleton disruption and tumor growth, while constitutive hep activation further aggravates the tumor phenotype. Interestingly, generation of undead cells by apoptosis inhibition in these hep knockdown cells by p35 expression further leads to tumor development. Hence, we conclude that scrib knockdown in a large area of wing disc might have a ‘group-protection’ and ‘undead-cells’ microenvironment that modulates the action of JNK signalling resulting in tumor formation. Furthermore, JNK dependent activation of Wnt/Ca2+ signalling also supports the tumor growth and actin cytoskeleton disruption. Thus, our results importantly highlight the role of JNK signalling in tumor progression upon scrib loss of function depending on cellular-microenvironment.

scholarly journals Anti-Angiogenic Effects of Phytochemicals on miRNA Regulating Breast Cancer Progression

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 191 ◽  
Author(s):  
Elizabeth Varghese ◽  
Alena Liskova ◽  
Peter Kubatka ◽  
Samson Mathews Samuel ◽  
Dietrich Büsselberg
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Cancer Progression ◽  
Tumor Angiogenesis ◽  
Expression Profiles ◽  
Metabolic Reprogramming ◽  
Breast Cancers ◽  
Oncogenic Signaling ◽  
Metabolic Switch

Several phytochemicals have been identified for their role in modifying miRNA regulating tumor progression. miRNAs modulate the expression of several oncogenes and tumor suppressor genes including the genes that regulate tumor angiogenesis. Hypoxia inducible factor-1 alpha (HIF-1α) signaling is a central axis that activates oncogenic signaling and acts as a metabolic switch in endothelial cell (EC) driven tumor angiogenesis. Tumor angiogenesis driven by metabolic reprogramming of EC is crucial for tumor progression and metastasis in many different cancers, including breast cancers, and has been linked to aberrant miRNA expression profiles. In the current article, we identify different miRNAs that regulate tumor angiogenesis in the context of oncogenic signaling and metabolic reprogramming in ECs and review how selected phytochemicals could modulate miRNA levels to induce an anti-angiogenic action in breast cancer. Studies involving genistein, epigallocatechin gallate (EGCG) and resveratrol demonstrate the regulation of miRNA-21, miRNA-221/222 and miRNA-27, which are prognostic markers in triple negative breast cancers (TNBCs). Modulating the metabolic pathway is a novel strategy for controlling tumor angiogenesis and tumor growth. Cardamonin, curcumin and resveratrol exhibit their anti-angiogenic property by targeting the miRNAs that regulate EC metabolism. Here we suggest that using phytochemicals to target miRNAs, which in turn suppresses tumor angiogenesis, should have the potential to inhibit tumor growth, progression, invasion and metastasis and may be developed into an effective therapeutic strategy for the treatment of many different cancers where tumor angiogenesis plays a significant role in tumor growth and progression.

scholarly journals RNF141 interacts with KRAS to promote colorectal cancer progression

Oncogene ◽  
2021 ◽  
Author(s):  
Jiuna Zhang ◽  
Xiaoyu Jiang ◽  
Jie Yin ◽  
Shiying Dou ◽  
Xiaoli Xie ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Plasma Membrane ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Critical Role ◽  
Ring Finger ◽  
Immunohistochemical Analysis ◽  
Bimolecular Fluorescence Complementation

AbstractRING finger proteins (RNFs) play a critical role in cancer initiation and progression. RNF141 is a member of RNFs family; however, its clinical significance, roles, and mechanism in colorectal cancer (CRC) remain poorly understood. Here, we examined the expression of RNF141 in 64 pairs of CRC and adjacent normal tissues by real-time PCR, Western blot, and immunohistochemical analysis. We found that there was more expression of RNF141 in CRC tissue compared with its adjacent normal tissue and high RNF141 expression associated with T stage. In vivo and in vitro functional experiments were conducted and revealed the oncogenic role of RNF141 in CRC. RNF141 knockdown suppressed proliferation, arrested the cell cycle in the G1 phase, inhibited migration, invasion and HUVEC tube formation but promoted apoptosis, whereas RNF141 overexpression exerted the opposite effects in CRC cells. The subcutaneous xenograft models showed that RNF141 knockdown reduced tumor growth, but its overexpression promoted tumor growth. Mechanistically, liquid chromatography-tandem mass spectrometry indicated RNF141 interacted with KRAS, which was confirmed by Co-immunoprecipitation, Immunofluorescence assay. Further analysis with bimolecular fluorescence complementation (BiFC) and Glutathione-S-transferase (GST) pull-down assays showed that RNF141 could directly bind to KRAS. Importantly, the upregulation of RNF141 increased GTP-bound KRAS, but its knockdown resulted in a reduction accordingly. Next, we demonstrated that RNF141 induced KRAS activation via increasing its enrichment on the plasma membrane not altering total KRAS expression, which was facilitated by the interaction with LYPLA1. Moreover, KRAS silencing partially abolished the effect of RNF141 on cell proliferation and apoptosis. In addition, our findings presented that RNF141 functioned as an oncogene by upregulating KRAS activity in a manner of promoting KRAS enrichment on the plasma membrane in CRC.

scholarly journals Intrabodies targeting human papillomavirus 16 E6 and E7 oncoproteins for therapy of established HPV-associated tumors

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Francesca Paolini ◽  
Carla Amici ◽  
Mariantonia Carosi ◽  
Claudia Bonomo ◽  
Paola Di Bonito ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Antitumor Activity ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Cellular Transformation ◽  
Neoplastic Progression ◽  
Single Chain ◽  
Hpv16 E6 ◽  
Associated Lesions ◽  
E6 And E7

Abstract Background The oncogenic activity of the high risk human papillomavirus type 16 (HPV16) is fully dependent on the E6 and E7 viral oncoproteins produced during viral infection. The oncoproteins interfere with cellular homeostasis by promoting proliferation, inhibiting apoptosis and blocking epithelial differentiation, driving the infected cells towards neoplastic progression. The causal relationship between expression of E6/E7 and cellular transformation allows inhibiting the oncogenic process by hindering the activity of the two oncoproteins. We previously developed and characterized some antibodies in single-chain format (scFvs) against the HPV16 E6 and E7 proteins, and demonstrated both in vitro and in vivo their antitumor activity consisting of protective efficacy against tumor progression of HPV16-positive cells. Methods Envisioning clinical application of the best characterized anti-HPV16 E6 and –HPV16 E7 scFvs, we verified their activity in the therapeutic setting, on already implanted tumors. Recombinant plasmids expressing the anti-HPV16 E6 scFvI7 with nuclear targeting sequence, or the anti-HPV16 E7 scFv43M2 with endoplasmic reticulum targeting sequence were delivered by injection followed by electroporation to three different preclinical models using C57/BL6 mice, and their effect on tumor growth was investigated. In the first model, the HPV16+ TC-1 Luc cells were used to implant tumors in mice, and tumor growth was measured by luciferase activity; in the second model, a fourfold number of TC-1 cells was used to obtain more aggressively growing tumors; in the third model, the HPV16+ C3 cells where used to rise tumors in mice. To highlight the scFv possible mechanism of action, H&E and caspase-3 staining of tumor section were performed. Results We showed that both the anti-HPV16 E6 and HPV16 E7 scFvs tested were efficacious in delaying tumor progression in the three experimental models and that their antitumor activity seems to rely on driving tumor cells towards the apoptotic pathway. Conclusion Based on our study, two scFvs have been identified that could represent a safe and effective treatment for the therapy of HPV16-associated lesions. The mechanism underlying the scFv effectiveness appears to be leading cells towards death by apoptosis. Furthermore, the validity of electroporation, a methodology allowed for human treatment, to deliver scFvs to tumors was confirmed.

scholarly journals The Role of Cancer-Associated Fibroblasts in Tumor Progression

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1399
Author(s):  
Rushikesh S. Joshi ◽  
Samanvi S. Kanugula ◽  
Sweta Sudhir ◽  
Matheus P. Pereira ◽  
Saket Jain ◽  
...  
Keyword(s):  
Cancer Treatment ◽  
Tumor Progression ◽  
Cancer Progression ◽  
Immune Cell ◽  
Systemic Disease ◽  
Genomic Medicine ◽  
Therapeutic Targets ◽  
Therapy Resistance ◽  
Cancer Associated Fibroblasts ◽  
Breast Cancers

In the era of genomic medicine, cancer treatment has become more personalized as novel therapeutic targets and pathways are identified. Research over the past decade has shown the increasing importance of how the tumor microenvironment (TME) and the extracellular matrix (ECM), which is a major structural component of the TME, regulate oncogenic functions including tumor progression, metastasis, angiogenesis, therapy resistance, and immune cell modulation, amongst others. Within the TME, cancer-associated fibroblasts (CAFs) have been identified in several systemic cancers as critical regulators of the malignant cancer phenotype. This review of the literature comprehensively profiles the roles of CAFs implicated in gastrointestinal, endocrine, head and neck, skin, genitourinary, lung, and breast cancers. The ubiquitous presence of CAFs highlights their significance as modulators of cancer progression and has led to the subsequent characterization of potential therapeutic targets, which may help advance the cancer treatment paradigm to determine the next generation of cancer therapy. The aim of this review is to provide a detailed overview of the key roles that CAFs play in the scope of systemic disease, the mechanisms by which they enhance protumoral effects, and the primary CAF-related markers that may offer potential targets for novel therapeutics.

scholarly journals Iron-Bound Lipocalin-2 from Tumor-Associated Macrophages Drives Breast Cancer Progression Independent of Ferroportin

Metabolites ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 180
Author(s):  
Christina Mertens ◽  
Matthias Schnetz ◽  
Claudia Rehwald ◽  
Stephan Grein ◽  
Eiman Elwakeel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Lung Metastases ◽  
Expression Profiles ◽  
The Cancer Genome Atlas ◽  
Lipocalin 2 ◽  
Tumor Associated Macrophages

Macrophages supply iron to the breast tumor microenvironment by enforced secretion of lipocalin-2 (Lcn-2)-bound iron as well as the increased expression of the iron exporter ferroportin (FPN). We aimed at identifying the contribution of each pathway in supplying iron for the growing tumor, thereby fostering tumor progression. Analyzing the expression profiles of Lcn-2 and FPN using the spontaneous polyoma-middle-T oncogene (PyMT) breast cancer model as well as mining publicly available TCGA (The Cancer Genome Atlas) and GEO Series(GSE) datasets from the Gene Expression Omnibus database (GEO), we found no association between tumor parameters and Lcn-2 or FPN. However, stromal/macrophage-expression of Lcn-2 correlated with tumor onset, lung metastases, and recurrence, whereas FPN did not. While the total iron amount in wildtype and Lcn-2−/− PyMT tumors showed no difference, we observed that tumor-associated macrophages from Lcn-2−/− compared to wildtype tumors stored more iron. In contrast, Lcn-2−/− tumor cells accumulated less iron than their wildtype counterparts, translating into a low migratory and proliferative capacity of Lcn-2−/− tumor cells in a 3D tumor spheroid model in vitro. Our data suggest a pivotal role of Lcn-2 in tumor iron-management, affecting tumor growth. This study underscores the role of iron for tumor progression and the need for a better understanding of iron-targeted therapy approaches.

scholarly journals Aging of Bone Marrow Mesenchymal Stromal Cells: Hematopoiesis Disturbances and Potential Role in the Development of Hematologic Cancers

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 68
Author(s):  
Fulvio Massaro ◽  
Florent Corrillon ◽  
Basile Stamatopoulos ◽  
Nathalie Meuleman ◽  
Laurence Lagneaux ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tumor Progression ◽  
Cancer Progression ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Cell Communication ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Wide Range ◽  
Major Player

Aging of bone marrow is a complex process that is involved in the development of many diseases, including hematologic cancers. The results obtained in this field of research, year after year, underline the important role of cross-talk between hematopoietic stem cells and their close environment. In bone marrow, mesenchymal stromal cells (MSCs) are a major player in cell-to-cell communication, presenting a wide range of functionalities, sometimes opposite, depending on the environmental conditions. Although these cells are actively studied for their therapeutic properties, their role in tumor progression remains unclear. One of the reasons for this is that the aging of MSCs has a direct impact on their behavior and on hematopoiesis. In addition, tumor progression is accompanied by dynamic remodeling of the bone marrow niche that may interfere with MSC functions. The present review presents the main features of MSC senescence in bone marrow and their implications in hematologic cancer progression.

scholarly journals POU2F2 promotes the proliferation and motility of lung cancer cells by activating AGO1

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ronggang Luo ◽  
Yi Zhuo ◽  
Quan Du ◽  
Rendong Xiao
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Human Lung ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
Cancer Tissues

Abstract Background To detect and investigate the expression of POU domain class 2 transcription factor 2 (POU2F2) in human lung cancer tissues, its role in lung cancer progression, and the potential mechanisms. Methods Immunohistochemical (IHC) assays were conducted to assess the expression of POU2F2 in human lung cancer tissues. Immunoblot assays were performed to assess the expression levels of POU2F2 in human lung cancer tissues and cell lines. CCK-8, colony formation, and transwell-migration/invasion assays were conducted to detect the effects of POU2F2 and AGO1 on the proliferaion and motility of A549 and H1299 cells in vitro. CHIP and luciferase assays were performed for the mechanism study. A tumor xenotransplantation model was used to detect the effects of POU2F2 on tumor growth in vivo. Results We found POU2F2 was highly expressed in human lung cancer tissues and cell lines, and associated with the lung cancer patients’ prognosis and clinical features. POU2F2 promoted the proliferation, and motility of lung cancer cells via targeting AGO1 in vitro. Additionally, POU2F2 promoted tumor growth of lung cancer cells via AGO1 in vivo. Conclusion We found POU2F2 was highly expressed in lung cancer cells and confirmed the involvement of POU2F2 in lung cancer progression, and thought POU2F2 could act as a potential therapeutic target for lung cancer.

scholarly journals Stromal CCL5 Promotes Breast Cancer Progression by Interacting with CCR3 in Tumor Cells

2021 ◽  
Vol 22 (4) ◽  
pp. 1918
Author(s):  
Mio Yamaguchi ◽  
Kiyoshi Takagi ◽  
Koki Narita ◽  
Yasuhiro Miki ◽  
Yoshiaki Onodera ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Carcinoma ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Stromal Cells ◽  
Human Breast Carcinoma ◽  
Breast Cancer Patients ◽  
Breast Carcinomas ◽  
Human Breast

Chemokines secreted from stromal cells have important roles for interactions with carcinoma cells and regulating tumor progression. C-C motif chemokine ligand (CCL) 5 is expressed in various types of stromal cells and associated with tumor progression, interacting with C-C chemokine receptor (CCR) 1, 3 and 5 expressed in tumor cells. However, the expression on CCL5 and its receptors have so far not been well-examined in human breast carcinoma tissues. We therefore immunolocalized CCL5, as well as CCR1, 3 and 5, in 111 human breast carcinoma tissues and correlated them with clinicopathological characteristics. Stromal CCL5 immunoreactivity was significantly correlated with the aggressive phenotype of breast carcinomas. Importantly, this tendency was observed especially in the CCR3-positive group. Furthermore, the risk of recurrence was significantly higher in the patients with breast carcinomas positive for CCL5 and CCR3 but negative for CCR1 and CCR5, as compared with other patients. In summary, the CCL5-CCR3 axis might contribute to a worse prognosis in breast cancer patients, and these findings will contribute to a better understanding of the significance of the CCL5/CCRs axis in breast carcinoma microenvironment.

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