Transfer and Expression of Antioncogenes and Paraneoplastic Genes in Normal and Neoplastic Cells in Vitro and in Vivo

Histiocytic proliferative diseases are rare in cats, and their pathogenesis is poorly understood. In the present study, 25 cases of histiocytic sarcoma (HS) and 6 of feline progressive histiocytosis (FPH) were examined, and survival times were recorded in 19 cases. The immunophenotypes of tumor cells in these cases as well as of nonneoplastic feline histiocytes were characterized using formalin-fixed, paraffin-embedded tissues. An FPH cell line (AS-FPH01) and xenotransplant mouse model of FPH were also established. The median survival time of HS (150 days) was significantly shorter than that of FPH (470 days). Immunohistochemically, nonneoplastic histiocytes were immunopositive for various combinations of Iba-1, HLA-DR, E-cadherin, CD204, CD163, CD208, and MAC387. By immunohistochemistry, dermal interstitial dendritic cells (iDCs) and macrophages were CD204+/E-cadherin−, while epidermal Langerhans cells (LCs) were CD204−/E-cadherin+. Neoplastic cells of 4 FPH and 18 HS were CD204+/E-cadherin− (iDC/macrophage immunophenotype), while 2 FPH and 2 HS were CD204−/E-cadherin+ (LC immunophenotype), and 5 HS were CD204+/E-cadherin+ (LC-like cell immunophenotype). Furthermore, immunohistochemical and western blot analyses of AS-FPH01 cells derived from E-cadherin-negative FPH revealed that cultured cells were immunopositive for both CD204 and E-cadherin in vitro and in vivo. These results indicate that the neoplastic cells of feline HS and FPH were variably positive for iDC/macrophage and LC markers, and their immunophenotype changed in different microenvironments. The novel cell line established in the present study may serve as an experimental model of FPH that will enable further molecular and therapeutic studies on this disease.

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Breast tumor cells promotes the horizontal propagation of EMT, stemness, and metastasis by transferring the MAP17 protein between subsets of neoplastic cells

Oncogenesis ◽

10.1038/s41389-020-00280-0 ◽

2020 ◽

Vol 9 (10) ◽

Author(s):

José Manuel García-Heredia ◽

Daniel Otero-Albiol ◽

Marco Pérez ◽

Elena Pérez-Castejón ◽

Sandra Muñoz-Galván ◽

...

Keyword(s):

Tumor Progression ◽

Tumor Cells ◽

Epithelial Mesenchymal Transition ◽

Notch Pathway ◽

Metastatic Potential ◽

Tumor Evolution ◽

Neoplastic Cells ◽

Mesenchymal Transition

Abstract MAP17 (PDZK1IP1) is a small protein regulating inflammation and tumor progression, upregulated in a broad range of carcinomas. MAP17 levels increase during tumor progression in a large percentage of advanced tumors. In the present work, we explored the role of this protein shaping tumor evolution. Here we show that in breast cancer, cells increased MAP17 levels in tumors by demethylation induced multiple changes in gene expression through specific miRNAs downregulation. These miRNA changes are dependent on Notch pathway activation. As a consequence, epithelial mesenchymal transition (EMT) and stemness are induced promoting the metastatic potential of these cells both in vitro and in vivo. Furthermore, MAP17 increased the exosomes in tumor cells, where MAP17 was released as cargo, and this horizontal propagation also increased the EMT in the recipient cells. Importantly, an antibody against MAP17 in the media reduces the EMT and stemness alterations promoted by the conditioned media from MAP17-expressing cells. Therefore, MAP17 expression promotes the horizontal propagation of EMT and metastasis by transferring the MAP17 protein between subsets of neoplastic cells. Thus, MAP17 can be used to describe a new mechanism for cell malignity at distance, without the involvement of genetic or epigenetic modifications. MAP17 can also be taken in consideration as new target for metastatic high-grade breast tumors.

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In vitro and in vivo studies on potentiation of cytotoxic effects of anticancer drugs or cobalt 60 gamma ray by interferon on human neoplastic cells

Cancer ◽

10.1002/1097-0142(19841115)54:10<2262::aid-cncr2820541033>3.0.co;2-n ◽

1984 ◽

Vol 54 (10) ◽

pp. 2262-2267 ◽

Cited By ~ 41

Author(s):

Masayoshi Namba ◽

Shoichi Yamamoto ◽

Hiroyoshi Tanaka ◽

Toshinori Kanamori ◽

Masahiro Nobuhara ◽

...

Keyword(s):

Anticancer Drugs ◽

Gamma Ray ◽

In Vivo Studies ◽

Neoplastic Cells ◽

Cytotoxic Effects

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Mesenchymal Stromal Cells for Antineoplastic Drug Loading and Delivery

Medicines ◽

10.3390/medicines4040087 ◽

2017 ◽

Vol 4 (4) ◽

pp. 87 ◽

Cited By ~ 4

Author(s):

Francesco Petrella ◽

Isabella Rimoldi ◽

Stefania Rizzo ◽

Lorenzo Spaggiari

Keyword(s):

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Targeted Delivery ◽

Drug Loading ◽

Tumour Microenvironment ◽

Chemotherapeutic Agents ◽

Immunomodulatory Activity ◽

Neoplastic Cells

Mesenchymal stromal cells are a population of undifferentiated multipotent adult cells possessing extensive self-renewal properties and the potential to differentiate into a variety of mesenchymal lineage cells. They express broad anti-inflammatory and immunomodulatory activity on the immune system and after transplantation can interact with the surrounding microenvironment, promoting tissue healing and regeneration. For this reason, mesenchymal stromal cells have been widely used in regenerative medicine, both in preclinical and clinical settings. Another clinical application of mesenchymal stromal cells is the targeted delivery of chemotherapeutic agents to neoplastic cells, maximizing the cytotoxic activity against cancer cells and minimizing collateral damage to non-neoplastic tissues. Mesenchymal stem cells are home to the stroma of several primary and metastatic neoplasms and hence can be used as vectors for targeted delivery of antineoplastic drugs to the tumour microenvironment, thereby reducing systemic toxicity and maximizing antitumour effects. Paclitaxel and gemcitabine are the chemotherapeutic drugs best loaded by mesenchymal stromal cells and delivered to neoplastic cells, whereas other agents, like pemetrexed, are not internalized by mesenchymal stromal cells and therefore are not suitable for advanced antineoplastic therapy. This review focuses on the state of the art of advanced antineoplastic cell therapy and its future perspectives, emphasizing in vitro and in vivo preclinical results and future clinical applications.

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Differential regulation of the TRH gene promoter by triiodothyronine and dexamethasone in pancreatic islets

Journal of Endocrinology ◽

10.1677/joe.0.1700091 ◽

2001 ◽

Vol 170 (1) ◽

pp. 91-98 ◽

Cited By ~ 4

Author(s):

P Fragner ◽

SL Lee ◽

S Aratan de Leon

Keyword(s):

Gene Expression ◽

Pancreatic Islets ◽

Promoter Activity ◽

Gene Promoter ◽

Luciferase Reporter ◽

Flanking Sequence ◽

Luciferase Reporter Gene ◽

Neoplastic Cells

TRH was initially found in the hypothalamus and regulates TSH secretion. TRH is also produced by insulin-containing beta-cells. Endogenous TRH positively regulates glucagon secretion and attenuates pancreatic exocrine secretion. We have previously shown that triiodothyronine (T(3)) down-regulates pre-pro-TRH gene expression in vivo and in vitro. The present study was designed to determine the initial impact of T(3) on rat TRH gene promoter and to compare this effect with that of dexamethasone (Dex). Primary islet cells and neoplastic cells (HIT T-15 and RIN m5F) were transiently transfected with fragments of the 5'-flanking sequence of TRH fused to the luciferase reporter gene. The persistence of high TRH concentrations in fetal islets in culture, probably due to transactivating factors, allowed us to explore how T(3) and Dex regulate the TRH promoter activity in transfected cells and whether the hormone effect is dependent on the cell type considered. TRH gene promoter activity is inhibited by T(3) in primary but not neoplastic cells and stimulated by Dex in both primary and neoplastic cells of islets. These findings validate previous in vivo and in vitro studies and indicate the transcriptional impact of these hormones on TRH gene expression in the pancreatic islets.

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Exogenously administered gangliosides fail to increase in vivo metastatic frequency or in vitro growth of murine neoplastic cells

Clinical & Experimental Metastasis ◽

10.1007/bf00117791 ◽

1990 ◽

Vol 8 (2) ◽

pp. 181-192 ◽

Cited By ~ 4

Author(s):

L. Facci ◽

S.D. Skaper ◽

D. Presti ◽

G. Kirschner ◽

A. Leon ◽

...

Keyword(s):

In Vitro Growth ◽

Neoplastic Cells

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Inhibition of the Axl pathway impairs breast and prostate cancer metastasis to the bones and bone remodeling

Clinical & Experimental Metastasis ◽

10.1007/s10585-021-10093-z ◽

2021 ◽

Author(s):

Mai Tanaka ◽

Samantha S. Dykes ◽

Dietmar W. Siemann

Keyword(s):

Breast Cancer ◽

Cell Signaling ◽

Cancer Cell ◽

Cancer Metastasis ◽

Metastatic Potential ◽

Breast Cancers ◽

Neoplastic Cells ◽

Breast And Prostate Cancer

AbstractApproximately 90% of cancer-related deaths result from cancer metastasis. In prostate and breast cancers, bone is the most common site of cancer cell dissemination. Key steps in the metastatic cascade are promoted through upregulation of critical cell signaling pathways in neoplastic cells. The present study assessed the role of the receptor tyrosine kinase Axl in prostate and breast cancer cell metastasis to bones using (i) Axl knockdown neoplastic cells and osteoclast progenitor cells in vitro, (ii) intracardiac injection of Axl knockdown tumor cells in vivo, and (iii) selective Axl inhibitor BGB324. Axl inhibition in neoplastic cells significantly decreased their metastatic potential, and suppression of Axl signaling in osteoclast precursor cells also reduced the formation of mature osteoclasts. In vivo, Axl knockdown in prostate and breast cancer cells significantly suppressed the formation and progression of bone metastases. Hence, therapeutic targeting of Axl may impair tumor metastasis to the bones through neoplastic and host cell signaling axes.

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A nanoformulation of siRNA and its role in cancer therapy: In vitro and in vivo evaluation

Cellular & Molecular Biology Letters ◽

10.2478/s11658-012-0043-2 ◽

2013 ◽

Vol 18 (1) ◽

Cited By ~ 17

Author(s):

Hitesh Jagani ◽

Josyula Rao ◽

Vasanth Palanimuthu ◽

Raghu Hariharapura ◽

Sagar Gang

Keyword(s):

Chitosan Nanoparticles ◽

Cancer Drugs ◽

Neoplastic Cells ◽

In Vivo Evaluation ◽

Anti Cancer ◽

Effective Delivery ◽

Interfering Rna ◽

Cancerous Cells

AbstractOverexpression of anti-apoptotic Bcl-2 is often observed in a wide variety of human cancers. It prevents the induction of apoptosis in neoplastic cells and contributes to resistance to chemotherapy. RNA interference has emerged as an efficient and selective technique for gene silencing. The potential to use small interfering RNA (siRNA) as a therapeutic agent for the treatment of cancer has elicited a great deal of interest. However, insufficient cellular uptake and poor stability have limited its therapeutic applications. The purpose of this study was to prepare chitosan nanoparticles via ionic gelation of chitosan by tripolyphosphate for effective delivery of siRNA to silence the anti-apoptotic Bcl-2 gene in neoplastic cells. Chitosan nanoparticles loaded with siRNA were in the size range 190 to 340 nm with a polydispersive index ranging from 0.04 to 0.2. They were able to completely bind with siRNA, provide protection against nuclease degradation, and enhance the transfection. Cell culture studies revealed that nanoparticles with entrapped siRNA could efficiently silence the antiapoptotic Bcl-2 gene. Studies on Swiss albino mice showed that siRNA could be effectively delivered through nanoparticles. There was significant decrease in the tumor volume. Blocking the expression of anti-apoptotic Bcl-2 can enhance the sensitivity of cancerous cells to anti-cancer drugs and the apoptosis rate. Therefore, nanoformulations with siRNA can be promoted as an adjuvant therapy in combination with anti-cancer drugs.

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Vitamin K3 Selectively Induces Apoptosis in Acute Lymphoblastic Leukemia Cells with Constitutive Activation of IKKα/NF-kB Activation.

Blood ◽

10.1182/blood.v106.11.859.859 ◽

2005 ◽

Vol 106 (11) ◽

pp. 859-859

Author(s):

Ningxi Zhu ◽

Lubing Gu ◽

Harry W. Findley ◽

Kuang-Yueh Chiang ◽

Muxiang Zhou

Keyword(s):

Cell Death ◽

Acute Lymphoblastic Leukemia ◽

Cell Lines ◽

Cytotoxic Effect ◽

Human Cancer ◽

Lymphoblastic Leukemia ◽

Vitamin K3 ◽

Neoplastic Cells

Abstract Although the cytotoxic effect of vitamin K3 (VK3) on human cancer cells has been repeatedly reported, no clear conclusions from either in vitro or in vivo tests have so far been made for VK3 as an anticancer agent due to marked inter-tumor variability of efficacy in response to VK3 treatment. Here, we report that sensitivity of neoplastic cells to VK3-induced killing depends on IKKα expression/NF-kB activation in the cells. We tested the sensitivity to VK3 of 14 leukemic cell lines established from children with acute lymphoblastic leukemia (ALL). The 14 lines were classified into three groups: IKKα +/NF-kB+, IKKα +/NF-kB−, IKKα−/NF-kB−. IKKα +/NFkB+ cell lines that are generally resistant to doxorubicin are more sensitive to VK3 induced cell death than are the IKKα +/NFkB− lines that are usually sensitive to doxorubicin. The median of IC 50 values of VK3 and doxorubicin as tested by WST analysis for IKKα +/NFkB+ cells were 3.92 mM and 1.58 mM, respectively, compared to IKKα +/NFkB− cells (7.3 mM of VK3 and 0.71 mM of doxorubicin, p<0.01, t-test). Assays by testing activation of caspase and cleavage of death substrate PARP as well as flow cytometry showed that apoptosis was induced in a line with high levels of IKKα/NF-kB activation at 2 h after VK3 treatment. In contrast, apoptosis was not induced by VK3 even at 48 h post-treatment in two lines that lack IKKa expression and NF-kB activation. To test if IKKα/NF-kB is a molecular target of VK3 inducing apoptosis in ALL, we examined the expression and activation of IKKα/NF-kB in VK3-treated cells. VK3 specifically reduced IKKα expression and inhibited NF-kB activation, resulting in downregulation of NF-kB-mediated gene expression and apoptosis. These results suggest that inhibition of IKKα/NF-kB signaling pathway is essential for VK3 to induce cell death, and that VK3, a dietary factor with no cytotoxic effect on normal cells, would be a useful adjuvant in the treatment of ALL and other cancer patients whose neoplastic cells express constitutive NF-kB and are resistant to chemotherapy.

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