scholarly journals Generation of a Novel Mesothelin-Targeted Oncolytic Herpes Virus and Implemented Strategies for Manufacturing

2021 ◽  
Vol 22 (2) ◽  
pp. 477
Author(s):  
Guendalina Froechlich ◽  
Chiara Gentile ◽  
Luigia Infante ◽  
Carmen Caiazza ◽  
Pasqualina Pagano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Reproductive System ◽  
Tumor Cell Line ◽  
Breast Tumors ◽  
Oncolytic Viruses ◽  
Female Reproductive System ◽  
Viral Glycoprotein ◽  
Preclinical Development ◽  
Biological Drugs

Background: HER2-based retargeted viruses are in advanced phases of preclinical development of breast cancer models. Mesothelin (MSLN) is a cell-surface tumor antigen expressed in different subtypes of breast and non-breast cancer. Its recent identification as a marker of some triple-negative breast tumors renders it an attractive target, presently investigated in clinical trials employing antibody drug conjugates and CAR-T cells. The availability of MSLN-retargeted oncolytic viruses may complement the current immunotherapeutic panel of biological drugs against HER2-negative breast and non-breast tumors. Methods: A fully virulent, tumor-targeted oncolytic Herpes simplex virus-1 (MSLN-THV) with a selectivity for mesothelin-expressing cancer cells was generated. Recombineering technology was used to replace an essential moiety of the viral glycoprotein D with antibody fragments derived from clinically validated MSLN monoclonal antibodies, and to allow IL12 cargo expression in infected cells. Panels of breast and female reproductive system cell lines were used to verify the oncolytic potential of the viral constructs. A platform for production of the retargeted viruses was developed in HEK 293 cells, providing stable expression of a suitable chimeric receptor. Results: We demonstrated the selectivity of viral infection and cytotoxicity by MSLN-retargeted viruses in a panel of mesothelin-positive cancer cells, originating from breast and female reproductive system tumors. We also developed a second-generation oncolytic MSLN-THV, encoding IL12, to enhance the immunotherapeutic potential of the viral backbone. A non-tumor cell line expressing a chimeric MSLN/Nectin-1 receptor, de-sensitized from antiviral responses by genetic inactivation of the Stimulator of Interferon Genes (STING)-dependent pathway was engineered, to optimize viral yields. Conclusions: Our proof-of-concept study proposes MSLN-retargeted herpesviruses as potential cancer immunotherapeutics for assessments in preclinical models of MSLN-positive tumors, complementing the available panel of oncolytic viruses to HER2-negative breast tumors.

scholarly journals Emerging roles of cancer-testis antigenes, semenogelin 1 and 2, in neoplastic cells

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Oleg Shuvalov ◽  
Alyona Kizenko ◽  
Alexey Petukhov ◽  
Olga Fedorova ◽  
Alexandra Daks ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Reproductive System ◽  
Seminal Fluid ◽  
Cancer Development ◽  
Migration And Invasion ◽  
Malignant Cells ◽  
Cancer Testis

AbstractCancer-testicular Antigens (CTAs) belong to a group of proteins that under normal conditions are strictly expressed in a male’s reproductive tissues. However, upon malignisation, they are frequently re-expressed in neoplastic tissues of various origin. A number of studies have shown that different CTAs affect growth, migration and invasion of tumor cells and favor cancer development and metastasis. Two members of the CTA group, Semenogelin 1 and 2 (SEMG1 and SEMG2, or SEMGs) represent the major component of human seminal fluid. They regulate the motility and capacitation of sperm. They are often re-expressed in different malignancies including breast cancer. However, there is almost no information about the functional properties of SEMGs in cancer cells. In this review, we highlight the role of SEMGs in the reproductive system and also summarize the data on their expression and functions in malignant cells of various origins.

scholarly journals TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth

2015 ◽  
Vol 112 (25) ◽  
pp. E3216-E3225 ◽  
Author(s):  
Svasti Haricharan ◽  
Powel Brown
Keyword(s):  
Breast Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Breast Tumors ◽  
Wild Type ◽  
Cancer Cell Growth ◽  
Breast Cancer Cell Growth ◽  
Tlr4 Activation

Breast cancer is a leading cause of cancer-related death, and it is important to understand pathways that drive the disease to devise effective therapeutic strategies. Our results show that Toll-like receptor 4 (TLR4) drives breast cancer cell growth differentially based on the presence of TP53, a tumor suppressor. TP53 is mutationally inactivated in most types of cancer and is mutated in 30–50% of diagnosed breast tumors. We demonstrate that TLR4 activation inhibits growth of TP53 wild-type cells, but promotes growth of TP53 mutant breast cancer cells by regulating proliferation. This differential effect is mediated by changes in tumor cell cytokine secretion. Whereas TLR4 activation in TP53 mutant breast cancer cells increases secretion of progrowth cytokines, TLR4 activation in TP53 wild-type breast cancer cells increases type I IFN (IFN-γ) secretion, which is both necessary and sufficient for mediating TLR4-induced growth inhibition. This study identifies a novel dichotomous role for TLR4 as a growth regulator and a modulator of tumor microenvironment in breast tumors. These results have translational relevance, demonstrating that TP53 mutant breast tumor growth can be suppressed by pharmacologic TLR4 inhibition, whereas TLR4 inhibitors may in fact promote growth of TP53 wild-type tumors. Furthermore, using data generated by The Cancer Genome Atlas consortium, we demonstrate that the effect of TP53 mutational status on TLR4 activity may extend to ovarian, colon, and lung cancers, among others, suggesting that the viability of TLR4 as a therapeutic target depends on TP53 status in many different tumor types.

scholarly journals Modulation of in Situ Estrogen Synthesis by Proline-, Glutamic Acid-, and Leucine-Rich Protein-1: Potential Estrogen Receptor Autocrine Signaling Loop in Breast Cancer Cells

2008 ◽  
Vol 22 (3) ◽  
pp. 649-664 ◽  
Author(s):  
Rajib Rajhans ◽  
Hareesh B. Nair ◽  
Sujit S. Nair ◽  
Valerie Cortez ◽  
Kijima Ikuko ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Glutamic Acid ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Breast Tumors ◽  
Aromatase Activity ◽  
Aromatase Expression ◽  
Estrogen Synthesis

Abstract In situ estrogen synthesis is implicated in tumor cell proliferation through autocrine or paracrine mechanisms especially in postmenopausal women. Several recent studies demonstrated activity of aromatase, an enzyme that plays a critical role in estrogen synthesis in breast tumors. Proline-, glutamic acid-, and leucine-rich protein-1 (PELP1/MNAR) is an estrogen receptor (ER) coregulator, and its expression is deregulated in breast tumors. In this study, we examined whether PELP1 promotes tumor growth by promoting local estrogen synthesis using breast cancer cells (MCF7) that stably overexpress PELP1. Immunohistochemistry revealed increased aromatase expression in MCF7-PELP1-induced xenograft tumors. Real-time PCR analysis showed enhanced activation of the aromatase promoter in MCF7-PELP1 clones compared with MCF7 cells. Using a tritiated-water release assay, we demonstrated that MCF7-PELP1 clones exhibit increased aromatase activity compared with control MCF-7 cells. PELP1 deregulation uniquely up-regulated aromatase expression via activation of aromatase promoter I.3/II, and growth factor signaling enhanced PELP1 activation of aromatase. PELP1-mediated induction of aromatase requires functional Src and phosphatidylinositol-3-kinase pathways. Mechanistic studies revealed that PELP1 interactions with ER-related receptor-α and proline-rich nuclear receptor coregulatory protein 2 lead to activation of aromatase. Immunohistochemistry analysis of breast tumor array showed increased expression of aromatase in ductal carcinoma in situ and node-positive tumors compared with no or weak expression in normal breast tissue. Fifty-four percent (n = 79) of PELP1-overexpressing tumors also overexpressed aromatase compared with 36% (n = 47) in PELP1 low-expressing tumors. Our results suggest that PELP1 regulation of aromatase represents a novel mechanism for in situ estrogen synthesis leading to tumor proliferation by autocrine loop and open a new avenue for ablating local aromatase activity in breast tumors.

scholarly journals Triple-Negative Breast Cancer Cells Recruit Neutrophils by Secreting TGF-β and CXCR2 Ligands

2021 ◽  
Vol 12 ◽  
Author(s):  
Shuvasree SenGupta ◽  
Lauren E. Hein ◽  
Yang Xu ◽  
Jason Zhang ◽  
Jamie R. Konwerski ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Neutrophil Migration ◽  
Breast Tumors ◽  
Malignant Potential ◽  
Tnbc Cell

Tumor associated neutrophils (TANs) are frequently detected in triple-negative breast cancer (TNBC). Recent studies also reveal the importance of neutrophils in promoting tumor progression and metastasis during breast cancer. However, the mechanisms regulating neutrophil trafficking to breast tumors are less clear. We sought to determine whether neutrophil trafficking to breast tumors is determined directly by the malignant potential of cancer cells. We found that tumor conditioned media (TCM) harvested from highly aggressive, metastatic TNBC cells induced a polarized morphology and robust neutrophil migration, while TCM derived from poorly aggressive estrogen receptor positive (ER+) breast cancer cells had no activity. In a three-dimensional (3D) type-I collagen matrix, neutrophils migrated toward TCM from aggressive breast cancer cells with increased velocity and directionality. Moreover, in a neutrophil-tumor spheroid co-culture system, neutrophils migrated with increased directionality towards spheroids generated from TNBC cells compared to ER+ cells. Based on these findings, we next sought to characterize the active factors secreted by TNBC cell lines. We found that TCM-induced neutrophil migration is dependent on tumor-derived chemokines, and screening TCM elution fractions based on their ability to induce polarized neutrophil morphology revealed the molecular weight of the active factors to be around 12 kDa. TCM from TNBC cell lines contained copious amounts of GRO (CXCL1/2/3) chemokines and TGF-β cytokines compared to ER+ cell-derived TCM. TCM activity was inhibited by simultaneously blocking receptors specific to GRO chemokines and TGF-β, while the activity remained intact in the presence of either single receptor inhibitor. Together, our findings establish a direct link between the malignant potential of breast cancer cells and their ability to induce neutrophil migration. Our study also uncovers a novel coordinated function of TGF-β and GRO chemokines responsible for guiding neutrophil trafficking to the breast tumor.

scholarly journals Polineoplasia in patients with cervical cancer in the Chelyabinsk region of Russia

2018 ◽  
Vol 5 (4) ◽  
pp. 8-17
Author(s):  
S. A. Bekhtereva ◽  
A. S. Domogirova ◽  
A. V. Vazhenin ◽  
I. A. Aksenova
Keyword(s):  
Breast Cancer ◽  
Cervical Cancer ◽  
Reproductive System ◽  
Survival Rates ◽  
Cervix Uteri ◽  
Female Reproductive System ◽  
Synchronous Tumors ◽  
Cumulative Survival ◽  
Chelyabinsk Region ◽  
Metachronous Tumors

The purpose of the study was to analyze the incidence of primary-multiple cancer (PMC) of the female reproductive system according to the population cancer register of the Chelyabinsk region for 15 years (1999-2013) using the example of PMC of the cervix. Carry out an analysis of the adjusted cumulative survival in the group of patients with PMC of the cervix as compared with solitary cervical cancer.Material and methods. The material was processed using the classification of Zisman I. F. and Kirichenko G. D. (1978) on the sequence of tumors: metachronous, synchronous, mechatronic-synchronous and synchronous-metachronous. The interval of metachronousness is 6 months. The survival rates of cancer patients in the Chelyabinsk region were calculated automatically with the use of the computer program "Calculation of survival rates" — an application to the population-based cancer registry of OOO Novell-SPb. Using the method of continuous sampling, we carried out a retrospective analysis of the case histories of patients with PMC of the female reproductive system treated in the SBEO CRCOD for 15 years (1999-2013).Results. During the period under review, 82 patients with PMC of the cervix uteri were examined, metachronous tumors prevailed in 55 (67.1%), synchronous tumors developed in 27 (33.75%). In the group of metachronous tumors in 12 (21.8%) patients had a combination of three tumors. Three (5.45%) patients had a combination of four tumors. Analysis of combinations of cervical cancer showed that more often, the cervical cancer metachronically met with breast cancer 35% (14 patients), endometrial cancer 17.5% (7 patients), ovarian cancer 7.5% (3 patients). Synchronously cervical cancer was more often combined with breast cancer 42.8% (9 patients), endometrium 28.6% (6 patients), ovaries 23.8% (5 patients) and rectal cancer 4.8% (1 patient).The results of calculation of the index of the adjusted cumulative survival of the study group of the PMC of the cervix showed that in the group of metachronous tumors, survival rates were significantly higher than in the group of synchronous tumors: single-year survival was 84.8 ± 6.3% against 82.4 ± 9.2, three-year survival — 66.8 ± 7.8% against 47, 1 ± 12.1, and five years after the diagnosis, 53.8 ± 8.6% of patients survived.Conclusion. Thus, patients with cervical cancer are at risk of developing cancer of other localizations that share common etiopathogenetic factors, such as HPV infection in women, hormonal disorders.

The role of atypical chemokine receptor-1 in breast cancer immune response.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23072-e23072 ◽  
Author(s):  
Rachel Martini ◽  
Petros Nikolinakos ◽  
Jamie Hodgson ◽  
Brittany Jenkins ◽  
Melissa Davis
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Chemokine Receptor ◽  
Immune Cells ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Breast Tumors ◽  
Human Breast ◽  
Inflammatory Chemokines

e23072 Background: Interactions between chemokines and their receptors can regulate anti-tumor response by influencing the migration of immune cells. Atypical Chemokine Receptor 1 (ACKR1/DARC), a genetically diverse transmembrane GPCR, acts as a decoy receptor for a variety of CXC and CC chemokines, including those with pro-malignant and pro-inflammatory effects, such as CCL2 and CXCL8 . The purpose of this study is to determine if the migration of tumor-associated immune cells is unique based on epithelial ACKR1 expression on breast cancer cells, and if this association is correlated to an increase in pro-malignant chemokines, survival, or race. Methods: Immunohistochemistry techniques were used to determine expression of ACKR1 on primary breast tumors, along with T-cells, B-cells, dendritic cells, and macrophages. Concentrations of pro-inflammatory chemokines in circulation were determined using a Luminex-based immunoassay. In silco analyses were performed to determine associations between ACKR1 tumor status, race, and survival. Finally, using human breast cancer cell lines and immunofluorescence techniques, co-localization between ACKR1 and pro-inflammatory chemokines was investigated. Results: Results from these tests indicate that there is differential infiltration of immune cell types in tumors expressing ACKR1, , which were not detected in ACKR1 negative tumors. Significantly increased circulating CCL2 and CXCL8 chemokine levels we also determined to be positively correlated with ACKR1 expression in primary breast tumors. Survival analyses showed a significantly increased relapse free survival in patients having tumors with high ACKR1 expression, while investigations into racial differences revealed a significant race effect, with Caucasians having higher ACKR1 levels on their tumors than African-Americans. Finally, co-localization between ACKR1 with CCL2 and CXCL8 is observed in cultured human breast cancer cells. Conclusions: tumors positively expressing ACKR1 to have a more favorable prognosis suggest that a role of ACKR1 on breast tumor cells is to sequester pro-inflammatory chemokines in the tumor microenvironment, recruiting a distinct subset of tumor-associated immune cells.

scholarly journals MRP8/ABCC11 Expression Is Regulated by Dexamethasone in Breast Cancer Cells and Is Associated to Progesterone Receptor Status in Breast Tumors

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Mylène Honorat ◽  
Aurélia Mesnier ◽  
Julie Vendrell ◽  
Attilio Di Pietro ◽  
Valérie Lin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Progesterone Receptor ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Breast Cancer Cells ◽  
Pregnane X Receptor ◽  
Breast Tumors ◽  
Mcf7 Cells ◽  
Protein Levels ◽  
Elevated Expression

The ATP-binding cassette multidrug resistance protein 8 (MRP8/ABCC11) mediates the excretion of anticancer drugs. ABCC11 mRNA and protein levels were enhanced by DEX (dexamethasone) and by PROG (progesterone) in MCF7 (progesterone receptor-(PR-) positive) but not in MDA-MB-231 (PR-negative) breast cancer cells. This suggested a PR-signaling pathway involvement in ABCC11 regulation. Nevertheless, pregnenolone-16α-carbonitrile (GR antagonist) and clotrimazole strongly and moderately decreased ABCC11 expression levels in Glucocortocoid Receptor-(GR-) and Pregnane X Receptor (PXR)-positive MCF7 cells but not in MDA-MB-231 cells (GR- and PXR-positive). Thus, GR-signaling pathway involvement could not be excluded in ABCC11 regulation in MCF7 cells. Furthermore, ABCC11 levels were positively correlated with the PR status of postmenopausal patient breast tumors from two independent cohorts. Thus, in the subclass of breast tumors (Estrogen Receptor-(ER-) negative/PR-positive), the elevated expression level of ABCC11 may alter the sensitivity to ABCC11 anticancer substrates, especially under treatment combinations with DEX.

scholarly journals Bone Marrow Stromal Antigen 2 (BST-2) DNA Is Demethylated in Breast Tumors and Breast Cancer Cells

PLoS ONE ◽  
2015 ◽  
Vol 10 (4) ◽  
pp. e0123931 ◽  
Author(s):  
Wadie D. Mahauad-Fernandez ◽  
Nicholas C. Borcherding ◽  
Weizhou Zhang ◽  
Chioma M. Okeoma
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Breast Tumors
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