scholarly journals Annexin II Interactions with the Annexin II Receptor Enhance Multiple Myeloma Cell Adhesion and Growth In the Bone Marrow Microenvironment

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 130-130 ◽  
Author(s):  
Sonia D'Souza ◽  
Noriyoshi Kurihara ◽  
Yusuke Shiozawa ◽  
Russell Taichman ◽  
Deborah Galson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Growth ◽  
Stromal Cells ◽  
Prostate Cancer Cell ◽  
Annexin Ii ◽  
Wild Type ◽  
Prostate Cancer Cells ◽  
Akt Phosphorylation

Abstract Abstract 130 Multiple myeloma (MM) is an incurable B-cell malignancy that develops in the bone marrow. The marrow microenvironment plays a critical role in supporting homing, lodging, and growth of MM cells by activating signaling pathways in both MM and bone marrow stromal cells (BMSC). Recently, we identified that annexin II (AXII) is involved in prostate cancer cell lodgment to the bone marrow as well as mobilization of prostate cancer cells to the peripheral blood. AXII expressed on stromal cells supports prostate cancer cell lodgment via the annexin II receptor (AXIIR) on prostate cancer cells. We hypothesized that MM cells use a similar mechanism to lodge and grow in the bone marrow. We demonstrated using bio-AXII, that MM cell lines and primary MM cells from 8 MM patients express the AXIIR protein. In addition, MM cells adhered significantly better to BMSC from wild-type mice than from AXII−/− mice. Knockdown of AXIIR by siRNA in MM.1S and ANBL.6 MM cells resulted in decreased AXII binding and decreased adherence of MM cells to KM101 stromal cells and BMSC from wild-type mice. Furthermore, the adhesion of MM.1SsiCon and MM.1SsiAXIIR cells to AXII−/− BMSC was similar indicating that AXII produced by MM cells does not act in an autocrine manner on attachment. Therefore, our studies indicate the importance of the interaction of AXII on BMSC with AXIIR on MM cells in adhesion. Our studies also revealed a role for AXIIR signaling on MM cell growth. We found that soluble AXII was released by osteoclasts into their conditioned media and stimulated the growth of MM cells via ERK1/2 and AKT phosphorylation in MM cells. AXII stimulation of MM cell growth was blocked by AXII antibody or by blocking ERK1/2 and AKT phosphorylation. In contrast, endogenous AXII produced by MM.1S cells did not stimulate MM.1S cell growth suggesting that autocrine AXII/AXIIR signaling in MM.1S cells does not contribute to MM.1S cell growth. Taken together, these results suggest that AXII/AXIIR axis in the myeloma microenvironment plays an important role in MM cell adhesion and growth through production of AXII by BMSC and osteoclasts. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Annexin II Interactions with the Annexin II Receptor Enhance Multiple Myeloma Cell Adhesion and Growth in the Bone Marrow Microenvironment,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3942-3942
Author(s):  
Sonia D'Souza ◽  
Noriyoshi Kurihara ◽  
Yusuke Shiozawa ◽  
Jeena Joseph ◽  
Russell Taichman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Growth ◽  
Cell Lines ◽  
Stromal Cells ◽  
Critical Role ◽  
Myeloma Cell ◽  
Bone Marrow Microenvironment ◽  
Annexin Ii

Abstract Abstract 3942 Background: Multiple myeloma (MM) is an incurable B-cell malignancy that develops in the bone marrow. The marrow microenvironment plays a critical role in supporting homing, lodging, and growth of MM cells by activating signaling pathways in both MM and bone marrow stromal cells (BMSC). We previously showed that annexin II (AXII) is involved in prostate cancer cell lodgment to the bone marrow via the annexin II receptor (AXIIR) expressed on prostate cancer cells. We hypothesized that MM cells use a similar mechanism to lodge and grow in the bone marrow. In support of this hypothesis, we found that MM cell lines and primary MM cells from 8 MM patients express the AXIIR protein, and that MM cells adhered significantly better to BMSC from AXII+/+ mice than from AXII−/− mice. Further, knockdown of AXIIR by siRNA in MM1.S and ANBL-6 MM cells decreased AXII binding and decreased adherence of MM cells to human stromal cells and BMSC from AXII+/+ mice. Furthermore, addition of an anti-AXII antibody to MM1.S cells, did not effect MM cell growth demonstrating that AXII expressed by MM cells does not support MM cell growth. Importantly, soluble AXII was released by osteoclasts into their conditioned media which stimulated the growth of MM cells via ERK1/2 and AKT phosphorylation. In the further study, we further characterized the role of AXIIR in MM-BMSC interactions. Methods: AXIIR expression in MM cells was determined by RT-PCR, Western blotting, and immunocytochemistry. Adhesion and growth assays were performed between MM cells and BMSC or AXII to determine the contribution of the AXII/AXIIR axis in supporting adhesion and growth of MM cells. In addition, MM cells or CD138+ cells from MM patients were treated with AXII to determine AXII-dependent MM cell growth. Further, adhesion and growth assays were performed on MM cells expressing either siAXIIR or shAXIIR. Phosphorylation assays were performed to determine the pathways stimulated by AXII in MM cells. Since OCL secrete large amount of AXII, MM cell growth assays were performed with OCL-CM from AXII+/+ and AXII−/− mice in the presence of an AXII antibody. Results: We now report that in addition to MM1.S and ANBL-6 cells, other MM cell lines, including U266, H929, and OPM2 also express AXIIR, and that AXII stimulated the growth of RPMI8226, ANBL-6 and U266 in addition to MM1.S cells. Finally, an AXIIR antibody prevented adhesion of MM1.S cells to AXII, and that AXII upregulated the adhesion molecule, RhoA in MM cells. Additionally, AXII did not stimulate the proliferation of MM1.SshAXIIR cells compared to MM1.SshControl or untreated MM cells, demonstrating that AXII specifically acts through its receptor, AXIIR on MM cells to promote proliferation. More importantly, AXII stimulated the growth of CD138+ cells obtained from MM patients. Conclusions: Based on our results, we conclude that the interaction between AXII and AXIIR in the bone marrow microenvironment supports adhesion via RhoA and growth of MM cells by stimulating the Erk1/2 and Akt pathways, AXII produced by MM cells does not act in an autocrine manner on MM cell growth. Thus, AXII and AXIIR are key players in MM and targeting the AXII/AXIIR axis may be a novel therapeutic approach for MM. Disclosures: Roodman: Amgen: Consultancy; Millennium: Consultancy.

scholarly journals Inhibition of glypican-1 expression induces an activated fibroblast phenotype in a human bone marrow-derived stromal cell-line

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sukhneeraj P. Kaur ◽  
Arti Verma ◽  
Hee. K. Lee ◽  
Lillie M. Barnett ◽  
Payaningal R. Somanath ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Marrow ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Stromal Cell ◽  
Prostate Cancer Cell ◽  
Bone Cells ◽  
Human Bone ◽  
Human Bone Marrow ◽  
Prostate Cancer Cells

AbstractCancer-associated fibroblasts (CAFs) are the most abundant stromal cell type in the tumor microenvironment. CAFs orchestrate tumor-stromal interactions, and contribute to cancer cell growth, metastasis, extracellular matrix (ECM) remodeling, angiogenesis, immunomodulation, and chemoresistance. However, CAFs have not been successfully targeted for the treatment of cancer. The current study elucidates the significance of glypican-1 (GPC-1), a heparan sulfate proteoglycan, in regulating the activation of human bone marrow-derived stromal cells (BSCs) of fibroblast lineage (HS-5). GPC-1 inhibition changed HS-5 cellular and nuclear morphology, and increased cell migration and contractility. GPC-1 inhibition also increased pro-inflammatory signaling and CAF marker expression. GPC-1 induced an activated fibroblast phenotype when HS-5 cells were exposed to prostate cancer cell conditioned media (CCM). Further, treatment of human bone-derived prostate cancer cells (PC-3) with CCM from HS-5 cells exhibiting GPC-1 loss increased prostate cancer cell aggressiveness. Finally, GPC-1 was expressed in mouse tibia bone cells and present during bone loss induced by mouse prostate cancer cells in a murine prostate cancer bone model. These data demonstrate that GPC-1 partially regulates the intrinsic and extrinsic phenotype of human BSCs and transformation into activated fibroblasts, identify novel functions of GPC-1, and suggest that GPC-1 expression in BSCs exerts inhibitory paracrine effects on the prostate cancer cells. This supports the hypothesis that GPC-1 may be a novel pharmacological target for developing anti-CAF therapeutics to control cancer.

Material properties of disulfide-crosslinked hyaluronic acid hydrogels influence prostate cancer cell growth and metabolism

2020 ◽  
Vol 8 (42) ◽  
pp. 9718-9733
Author(s):  
Nicky W. Tam ◽  
Dudley Chung ◽  
Samuel J. Baldwin ◽  
Jeffrey R. Simmons ◽  
Lingling Xu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Hyaluronic Acid ◽  
Cell Growth ◽  
Cancer Cells ◽  
Material Properties ◽  
Prostate Cancer Cell ◽  
Prostate Cancer Cells ◽  
Cancer Cell Growth ◽  
Diffusion Limited ◽  
Metastatic Cells

Studying prostate cancer cells embedded in hyaluronic acid hydrogels provides insight on how metastatic cells might behave in diffusion-limited tissue microenvironments.

scholarly journals Molecular signatures associated with prostate cancer cell line (PC-3) exposure to inactivated Zika virus

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Jeany Delafiori ◽  
Estela de Oliveira Lima ◽  
Mohamed Ziad Dabaja ◽  
Flávia Luísa Dias-Audibert ◽  
Diogo Noin de Oliveira ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Zika Virus ◽  
Prostate Cancer Cell ◽  
Antiproliferative Effect ◽  
Mass Spectrometry Analysis ◽  
Molecular Signatures ◽  
Prostate Cancer Cells

Abstract The recent outbreak of Zika virus (ZIKV) infection associated with microcephaly cases has elicited much research on the mechanisms involved in ZIKV-host cell interactions. It has been described that Zika virus impairs cell growth, raising a hypothesis about its oncolytic potential against cancer cells. ZIKV tumor cell growth inhibition was later confirmed for glioblastoma. It was also demonstrated that an inactivated ZIKV prototype (ZVp) based on bacterial outer membrane vesicles has antiproliferative activity upon other cancer cell lines, such as PC-3 prostate cancer cell. This study aims at understanding the pathways that might be involved with the antiproliferative effect of Zika virus against prostate cancer cells. A metabolomic approach based on high-resolution mass spectrometry analysis led to the identification of 21 statistically relevant markers of PC-3 cells treated with ZVp. The markers were associated with metabolic alterations that trigger lipid remodeling, endoplasmic reticulum stress, inflammatory mediators, as well as disrupted porphyrin and folate metabolism. These findings highlight molecular signatures of ZVp-induced response that may be involved on cellular pathways triggered by its antiproliferative effect. To our knowledge, this is the first reported metabolomic assessment of ZIKV effect on prostate cancer cells, a promising topic for further research.

Neutrophil-Secreted Proteinase 3 Mediates Metastasis of Prostate Cancer Cells Expressing RAGE to the Bone Marrow

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1025-1025 ◽  
Author(s):  
Mikhail Kolonin ◽  
Anna Sergeeva ◽  
Daniela Staquicini ◽  
Jeffrey J. Molldrem ◽  
Renata Pasqualini ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Marrow ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Prostate Cancer Cell ◽  
Human Prostate ◽  
Proteinase 3 ◽  
Human Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Cell Surfaces

Abstract Human prostate cancer non-randomly metastasizes to the bone marrow, but the biological basis for such site-specific tropism remains largely unresolved. Differential expression of molecules in the bone marrow microenvironment "niche" has recently been proposed to play a role. In previous work, combinatorial selection of random peptide libraries in end-of-life cancer patients has revealed an unexpected interaction between the receptor for advanced glycation end products (RAGE), a molecule expressed on malignant cell surfaces in advanced prostate cancer, and proteinase 3 (PR3), a serine protease abundantly present on neutrophils and promyelocytes within the bone marrow microenvironment. Because RAGE is selectively overexpressed in prostate cancer bone metastases, we hypothesize here that its specific binding to PR3 might mediate homing of prostate cancer cells to the bone marrow. We demonstrate that PR3 non-proteolytically binds to RAGE on prostate cancer cell surfaces and thereby promotes tumor cell activation and motility. We also show that the downstream signal transduction cascade triggered by RAGE/PR3 binding involves p44/42 (Erk1/2) and JNK1 phosphorylation. Finally, we use a mouse model of experimental metastasis to demonstrate that RAGE protein expression on human prostate cancer cells promotes their homing to bone marrow within a short time frame. These results validate a functional protein interaction between RAGE and PR3 and uncover a mechanism through which neutrophils mediate prostate cancer cell metastasis to the skeleton. Disclosures Sergeeva: Astellas: Patents & Royalties. Molldrem:Astellas Pharma: Patents & Royalties.

scholarly journals Annexin II interactions with the annexin II receptor enhance multiple myeloma cell adhesion and growth in the bone marrow microenvironment

Blood ◽  
2012 ◽  
Vol 119 (8) ◽  
pp. 1888-1896 ◽  
Author(s):  
Sonia D'Souza ◽  
Noriyoshi Kurihara ◽  
Yusuke Shiozawa ◽  
Jeena Joseph ◽  
Russell Taichman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Growth ◽  
Stromal Cells ◽  
Critical Role ◽  
Myeloma Cell ◽  
Annexin Ii ◽  
Multiple Myeloma Cell ◽  
B Cell Malignancy ◽  
Multiple Signaling

Abstract Multiple myeloma (MM) is an incurable B-cell malignancy in which the marrow microenvironment plays a critical role in our inability to cure MM. Marrow stromal cells in the microenvironment support homing, lodging, and growth of MM cells through activation of multiple signaling pathways in both MM and stromal cells. Recently, we identified annexin II (AXII) as a previously unknown factor produced by stromal cells and osteoclasts (OCL) that is involved in OCL formation, HSC and prostate cancer (PCa) homing to the BM as well as mobilization of HSC and PCa cells. AXII expressed on stromal cells supports PCa cell lodgment via the AXII receptor (AXIIR) on PCa cells, but the role of AXII and AXIIR in MM is unknown. In this study, we show that MM cells express AXIIR, that stromal/osteoblast-derived AXII facilitates adhesion of MM cells to stromal cells via AXIIR, and OCL-derived AXII enhances MM cell growth. Finally, we demonstrate that AXII activates the ERK1/2 and AKT pathways in MM cells to enhance MM cell growth. These results demonstrate that AXII and AXIIR play important roles in MM and that targeting the AXII/AXIIR axis may be a novel therapeutic approach for MM.

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