Bidirectional Notch Signaling and Osteocyte-Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma

Peritoneal cytological investigation was carried out inpatients with endometrial cancer, who were subjected to hysteroscopy before the operation (37patients) or were operated on without hysteroscopy. Comparative analysis of the data didnt reveal the role of hysteroscopy in tumor cell dissemination.

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The AP-1 transcription factor JunB is essential for multiple myeloma cell proliferation and drug resistance in the bone marrow microenvironment

Leukemia ◽

10.1038/leu.2016.358 ◽

2016 ◽

Vol 31 (7) ◽

pp. 1570-1581 ◽

Cited By ~ 23

Author(s):

F Fan ◽

M H Bashari ◽

E Morelli ◽

G Tonon ◽

S Malvestiti ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Cell Proliferation ◽

Drug Resistance ◽

Transcription Factor ◽

Myeloma Cell ◽

Bone Marrow Microenvironment ◽

Multiple Myeloma Cell

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Endothelial Cells Induce Multiple Myeloma Cell Proliferation Protect Against Conventional and Novel Therapies.

Blood ◽

10.1182/blood.v104.11.2354.2354 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2354-2354

Author(s):

Shaji Kumar ◽

Noopur Raje ◽

Teru Hideshima ◽

Klaus Podar ◽

Kenji Ishitsuka ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Proliferation ◽

Endothelial Cells ◽

Tumor Cell ◽

Blood Vessels ◽

Intracellular Signaling ◽

De Novo ◽

Cell Contact ◽

Protective Effects ◽

Tumor Cell Proliferation

Abstract Angiogenesis or formation of new blood vessels from existing blood vessels, in contrast to vasculogenesis or de novo formation of new vessels, plays an important role in the progression and spread of most cancers. Multiple myeloma (MM) is characterized by increased microvessel density (MVD), a quantitative estimate of angiogenesis, which correlates with stage of disease. MVD increases with progression from MGUS to smoldering MM to newly diagnosed MM and relapsed MM. It is a powerful prognostic factor, predicting for overall survival. To further elucidate the biological basis for the prognostic value of increased angiogenesis in MM, we studied the interactions of MM cells with endothelial cells using HUVECS as a model system. Co-culture of MM cells (MM1.S, OPM2, U266) with HUVECS induced tumor cell proliferation. Enhanced tumor cell proliferation correlated with the number of HUVECs and was greater than that triggered by co-culture with patient bone marrow stromal cells. When HUVECs were fixed prior to co-culture there was a significant decrease in the tumor cell proliferation. Addition of HUVEC conditioned media to the MM cell lines also induced proliferation. Importantly, HUVECS protected against anti-MM agents including conventional agents (Dexamethasone, Doxorubicin, Melphalan) and novel drugs (Revlimid™). The protective effect afforded by co-culture was lost on HUVEC fixation. Intracellular signaling events following MM cell-endothelial cell contact were studied to understand the mechanisms of the proliferative and protective effects. Western blotting demonstrated activation of the JAK/STAT, PI3K/Akt and the MAPK pathways, mediating proliferation and survival. Ongoing studies focused on understanding cytokine as well as adhesion-mediated interactions between the endothelial cells and the MM cells will identify targets for new therapeutic approaches in MM.

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Crosstalk Between Notch and CD80/86 Signaling In Multiple Myeloma

Blood ◽

10.1182/blood.v118.21.1111.1111 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1111-1111

Author(s):

Chandana Koorella ◽

Jayakumar R Nair ◽

Louise M Carlson ◽

Kelvin P. Lee

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

T Cells ◽

Dendritic Cells ◽

Notch Signaling ◽

Plasma Cells ◽

Casein Kinase Ii ◽

Pi3k Pathway ◽

Casein Kinase ◽

Bone Marrow Microenvironment

Abstract Abstract 1111 Multiple myeloma is a neoplasm of bone marrow resident plasma cells characterized by its dependence on the bone marrow microenvironment (BME) for production of survival factors including IL-6, a prototypic cytokine in myeloma biology. However, little is known about the molecular and cellular components of the BME involved in IL-6 production. At the cellular level, we and others have previously shown that dendritic cells (DC)-expressing CD80/CD86 (ligands with short cytoplasmic tails and signaling partners of CD28 expressed on myeloma cells) - in the bone marrow microenvironment have been implicated as being an important component. At the molecular level, the CD28-CD80/86 and Notch1-Jagged2 pathways were separately implicated by us (in DC) and others (in stromal cells) in myeloma induced IL-6 production. Blocking either of the pathways causes significant decrease in IL-6 production suggesting crosstalk between the two pathways. To test our hypothesis, DC were stimulated with CD28-Ig (a soluble form of CD28 which mimicks myeloma cell-bound CD28) in the presence or absence of an inhibitor of Notch signaling -DAPT. DC treated with CD28-Ig and DAPT significantly downregulated IL-6 production when compared to DC treated with CD28-Ig alone. This decrease was not due to the decrease in CD80/86 expression on DC. Our results suggest that CD28 mediated IL-6 production is dependent on Notch signaling and crosstalk between the Notch1-Jagged2 and CD28-CD80/86 pathways leads to IL-6 production by DC. Crosstalk between CD28-CD80/86 and Notch1-Jagged2 pathways was also observed in murine bone marrow derived dendritic cells (BMDC), where a significant down regulation of IL-6 was observed upon blocking Notch signaling. One possible mechanism of crosstalk involves direct effect of CD80/86 crosslinking by CD28-Ig on Notch expression/signaling leading to increase in IL-6 production. We tested for this possibility in DC and found no significant change in Notch expression/signaling. We thus hypothesized that the mechanism of crosstalk involves molecules downstream of Notch and/or CD80/86. Notch signaling has been reported to be involved in the regulation of PTEN (a negative regulator of the PI3K/Akt pathway). Previous studies have also shown the importance of FoxO3a-a transcription factor tightly regulated by Akt- in regulating IL-6 production in BMDC upon CD80/86 crosslinking. We therefore tested the possible involvement of PTEN (molecule downstream of Notch signaling), PI3K-Akt-FoxO3a axis (downstream of CD80/86) in crosstalk between the two pathways aforementioned by testing the effect of GSI on their regulation at the protein level. Blocking PI3K causes significant decrease in IL-6 production by DC and also decreases phosphorylation of Akt and FoxO3a. Similarly results were observed with blocking Akt activation. Blocking Notch signaling downregulates activation of p-Akt and p-FoxO3a suggesting that crosstalk between Notch-CD80/86 signaling involves PI3K-Akt-FoxO3a axis. Additionally, Notch regulates PI3K pathway via inactivation of PTEN and activation of casein kinase II (a molecule known to phosphorylate PTEN). We propose a model of crosstalk between Notch and CD80/86 signaling involving negative regulation of PTEN (which in turn is regulated by casein kinase II) which drives IL-6 production by PI3K-Akt-FoxO3a upon crosslinking CD80/86 by CD28-Ig. We have previously reported that in the myeloma BME, DC backsignaling via CD80/86 is also involved in production of indoleamine 2, 3 dioxygenase (IDO), an immunosuppressive enzyme which breaks down tryptophan to L-kynurenine rendering T cells inactive. To test if the model of crosstalk between Notch and CD80/86 signaling is similar in IDO activity, we treated DC with CTLA4-Ig with DAPT/PI3K inhibitor and found significant downregulation of IDO activity suggesting the involvement of PI3K pathway in crosstalk. Though the median survival and progression-free survival of myeloma patients has doubled over the past decade, it remains incurable prompting the need for finding new targets. Our work helps decipher molecules involved in IL-6 and IDO (important cytokines in myeloma biology) production in the BME of myeloma thus providing novel therapeutic targets. Furthermore, expression of CD28 on T cells and long lived plasma cells (as shown by us previously) helps extend our model of crosstalk to understanding their biology as well. Disclosures: No relevant conflicts of interest to declare.

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GW654652, the pan-inhibitor of VEGF receptors, blocks the growth and migration of multiple myeloma cells in the bone marrow microenvironment

Blood ◽

10.1182/blood-2003-10-3527 ◽

2004 ◽

Vol 103 (9) ◽

pp. 3474-3479 ◽

Cited By ~ 58

Author(s):

Klaus Podar ◽

Laurence P. Catley ◽

Yu-Tzu Tai ◽

Reshma Shringarpure ◽

Pedro Carvalho ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Cell Proliferation ◽

Protein Kinase ◽

Tyrosine Kinase ◽

Bone Marrow Microenvironment ◽

Vegf Receptor ◽

Vegf Receptors ◽

And Migration ◽

Dependent Pathway

Abstract Previous studies have shown that the multiple myeloma (MM) cell line and MM patient cells express high-affinity vascular endothelial growth factor (VEGF) receptor-1 or Fms-like tyrosine kinase-1 (Flt-1) but not VEGF receptor-2 or Flk-1/kinase insert domain-containing receptor (Flk-1/KDR) and that VEGF triggers MM cell proliferation through a mitogen-activated protein kinase (MAPK)-dependent pathway and migration through a protein kinase C (PKC)-dependent pathway. The present study evaluates the efficacy of the small molecule tyrosine-kinase inhibitor GW654652, which inhibits all 3 VEGF receptors with similar potency. We show that GW654652 acts directly on MM cells and in the bone marrow microenvironment. Specifically, GW654652 (1-10 μg/mL) inhibits, in a dose-dependent fashion, VEGF-triggered migrational activity and cell proliferation of MM cell lines that are sensitive and resistant to conventional therapy. As expected from our previous studies of VEGF-induced signaling and sequelae in MM cells, GW654652 blocked VEGF-induced Flt-1 phosphorylation and downstream activation of AKT-1 and MAPK-signaling cascades. Importantly, GW654652 also inhibits interleukin-6 and VEGF secretion and proliferation of MM cells induced by tumor cell binding to bone marrow (BM) stromal cells. The activity of a pan-VEGF receptor inhibitor against MM cells in the BM milieu, coupled with its lack of major toxicity in preclinical mouse models, provides the framework for clinical trials of this drug class to improve patient outcome in MM. (Blood. 2004;103:3474-3479)

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Cancer-Preventive Role of Bone Marrow-Derived Mesenchymal Stem Cells on Colitis-Associated Colorectal Cancer: Roles of Gut Microbiota Involved

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.642948 ◽

2021 ◽

Vol 9 ◽

Author(s):

Ruohang He ◽

Chaoqun Han ◽

Ying Li ◽

Wei Qian ◽

Xiaohua Hou

Keyword(s):

Colorectal Cancer ◽

Stem Cells ◽

Bone Marrow ◽

Cell Proliferation ◽

Mesenchymal Stem Cells ◽

Tumor Cell ◽

Rna Sequencing ◽

Ribosomal Rna ◽

Tumor Cell Proliferation

BackgroundMesenchymal stem cells (MSCs) treatment showed promising results in inflammatory bowel disease in both rodent models and patients. Nevertheless, previous studies conducted conflicting results on preclinical tumor models treated with MSCs concerning their influence on tumor initiation and progression. This study is designed to demonstrate the role of bone marrow-derived MSCs and the potential mechanism in the colitis-associated colon cancer (CAC) model.MethodsBone marrow-derived MSCs were isolated from green fluorescent protein-transgenic mice, cultured, and identified by flow cytometry. Azoxymethane and dextran sulfate sodium were administrated to establish the CAC mouse model, and MSCs were infused intraperitoneally once per week. The mice were weighed weekly, and colon length, tumor number, and average tumor size were assessed after the mice were killed. MSC localization was detected by immunofluorescence staining; tumor cell proliferation and apoptosis were measured by immunohistochemistry staining of Ki-67 and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay, respectively. The colonic tumor tissues were isolated for RNA-seq, and fecal samples were collected for 16S ribosomal RNA sequencing of the microbiome.ResultsAfter injection intraperitoneally, MSCs migrated to the intestine and inhibited the initiation of colitis-associated colorectal cancer. This inhibition effect was marked by less weight loss, longer colon length, and reduced tumor numbers. Moreover, MSCs reduced tumor cell proliferation and induced tumor cell apoptosis. Furthermore, MSCs could inhibit chronic inflammation assessed by RNA-sequencing and promote gut microbiome normalization detected by 16S ribosomal RNA sequencing.ConclusionThe results proved that MSCs could migrate to the colon, inhibit chronic inflammation, and regulate gut microbiome dysbiosis to suppress the development of CAC.

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