Novel surface targets and serum biomarkers from the ovarian cancer vasculature

Sasaroli, Dimitra; Gimotty, Phyllis A.; Pathak, Harsh B.; Hammond, Rachel; Kougioumtzidou, Eleni; Katsaros, Dionyssios; Buckanovich, R. J.; Devarajan, Karthik; Sandaltzopoulos, Raphael; Godwin, Andrew K.; Scholler, Nathalie; Coukos, George

doi:10.4161/cbt.12.3.16260

Cited by 39 publications

(28 citation statements)

References 34 publications

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“…ADAM12 has been reported to be upregulated in tumor-associated vasculature in ovarian (24,25), breast (26) and skin (8) tumors. However, whether ADAM12 promotes or contributes to tumor angiogenesis is unclear.…”

Section: Discussionmentioning

confidence: 99%

ADAM12 Is a Novel Regulator of Tumor Angiogenesis via STAT3 Signaling

Roy

Dagher

Butterfield

et al. 2017

Molecular Cancer Research

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ADAM12, (A Disintegrin and metalloproteinase domain-containing protein 12), is upregulated in epithelial cancers and contributes to increased tumor proliferation, metastasis and endocrine resistance. However, its role in tumor angiogenesis is unknown. Here we report that ADAM12 is upregulated in the vessels of aggressive breast tumors and exerts key regulatory functions. ADAM12 significantly increases bFGF-mediated angiogenesis in vivo and ADAM12 levels are upregulated in tumors that have undergone a switch to the angiogenic phenotype. Importantly, ADAM12-overexpressing breast tumors display a higher microvessel density (MVD). Our aim was to identify the mechanisms by which tumor-associated ADAM12 promotes angiogenesis. ADAM12 expression in breast tumor cells correlated with a significant upregulation of proangiogenic factors such as VEGF and MMP-9 and downregulation of antiangiogenic factors such as Thrombospondin-1 (THBS1/TSP1) and Tissue inhibitor of metalloproteinases-2 (TIMP-2). Co-culture with ADAM12-expressing tumor cells promoted endothelial cell (EC) recruitment and capillary tube formation. Conversely, downregulation of endogenous ADAM12 in breast cancer cell lines resulted in reduction of pro-angiogenic factors and EC recruitment. These ADAM12-mediated effects are driven by the activation of EGFR, STAT3 and Akt signaling. Blockade of EGFR/STAT3 or silencing of ADAM12 reversed the proangiogenic tumor phenotype, significantly downregulated pro-angiogenic mitogens and reduced EC recruitment. In human breast cancer tissues, ADAM12 expression was significantly positively correlated with pro-angiogenic factors including VEGF and MMP-9 but negatively associated with TSP1.

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Section: Discussionmentioning

confidence: 99%

ADAM12 Is a Novel Regulator of Tumor Angiogenesis via STAT3 Signaling

Roy

Dagher

Butterfield

et al. 2017

Molecular Cancer Research

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“…The feasibility of this approach was previously demonstrated by Lanitis and colleagues (22), who showed that split-signaling CAR T cells are only fully activated when both CARs are engaged. Additional tumor endothelial targets have been identified in ovarian cancer (4, 48) as well as other tumors (49), enabling such combinatorial designs.…”

Section: Discussionmentioning

confidence: 99%

T Cells Bearing a Chimeric Antigen Receptor against Prostate-Specific Membrane Antigen Mediate Vascular Disruption and Result in Tumor Regression

Santoro

Kim

Motz

et al. 2015

Cancer Immunology Research

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Aberrant blood vessels enable tumor growth, provide a barrier to immune infiltration, and serve as a source of pro-tumorigenic signals. Targeting tumor blood vessels for destruction, or tumor vascular disruption therapy, can therefore provide significant therapeutic benefit. Here we describe the ability of chimeric antigen receptor (CAR)-bearing T cells to recognize human prostate-specific membrane antigen (hPSMA) on endothelial targets in vitro as well as in vivo. CAR T cells were generated using the anti-PSMA scFv, J591, and the intracellular signaling domains: CD3ζ, CD28, and/or CD137/4-1BB. We found that all anti-hPSMA CAR T cells recognized and eliminated PSMA+ endothelial targets in vitro, regardless of the signaling domain. T cells bearing the 3rd generation anti-hPSMA CAR, P28BBζ, were able to recognize and kill primary human endothelial cells isolated from gynecologic cancers. In addition, the P28BBζ CAR T cells mediated regression of hPSMA-expressing vascular neoplasms in mice. Finally, in murine models of ovarian cancers populated by murine vessels expressing hPSMA, the P28BBζ CAR T cells were able to ablate PSMA+ vessels, cause secondary depletion of tumor cells, and reduce tumor burden. Taken together, these results provide strong rationale for the use of CAR T cells as agents of tumor vascular disruption, specifically those targeting PSMA.

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“…Our data also suggested that aberrant localization of CK-1a and keratin filament disassembly induced by FAM83H overexpression are involved in the migration of colorectal cancer cells. FAM83H overexpression was suggested in various types of cancer (Sasaroli et al, 2011), and CK-1a is known to play a tumor suppressive role (Elyada et al, 2011;Valenta et al, 2012). Thus, tumor progression of various types of cancer might be commonly promoted by FAM83H overexpression, malfunction of CK-1a and subsequent disassembly of keratin filaments.…”

Section: Discussionmentioning

confidence: 99%

“…However, very recent reports suggest the involvement of FAM83H in cancer. Microarray analysis of cancer tissues indicate increased expression of FAM83H in various types of cancer, including colorectal cancer (Sasaroli et al, 2011). Furthermore, Hatanaka and colleagues performed a focus formation assay using the cDNA library prepared from biliary tract cancer tissue and showed that fragmented FAM83H cDNA possesses transforming activity (Hatanaka et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

A novel mechanism of keratin cytoskeleton organization through casein kinase Iα and FAM83H in colorectal cancer

Kuga

Kume

Kawasaki

et al. 2013

Journal of Cell Science

134

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SummaryKeratin filaments form cytoskeletal networks in epithelial cells. Dynamic rearrangement of keratin filament networks is required for epithelial cells to perform cellular processes such as cell migration and polarization; however, the mechanism governing keratin filament rearrangement remains unclear. Here, we describe a novel mechanism of keratin cytoskeleton organization mediated by casein kinase Ia (CK-1a) and a newly identified keratin-associated protein, FAM83H. Knockdown of FAM83H induces keratin filament bundling, whereas overexpression of FAM83H disassembles keratin filaments, suggesting that FAM83H regulates the filamentous state of keratins. Intriguingly, keratin filament bundling is concomitant with the dissociation of CK-1a from keratin filaments, whereas aberrant speckle-like localization of CK-1a is observed concomitantly with keratin filament disassembly. Furthermore, CK-1a inhibition, similar to FAM83H knockdown, causes keratin filament bundling and reverses keratin filament disassembly induced by FAM83H overexpression, suggesting that CK-1a mediates FAM83H-dependent reorganization of keratin filaments. Because the N-terminal region of FAM83H interacts with CK-1a and the C-terminal region interacts with keratins, FAM83H might tether CK-1a to keratins. Colorectal cancer tissue also shows keratin filament disassembly accompanied with FAM83H overexpression and aberrant CK-1a localization, and FAM83H-overexpressing cancer cells exhibit loss or alteration of epithelial cell polarity. Importantly, knockdown of FAM83H inhibits cell migration accompanied by keratin cytoskeleton rearrangement in colorectal cancer cells. These results suggest that keratin cytoskeleton organization is regulated by FAM83H-mediated recruitment of CK-1a to keratins, and that keratin filament disassembly caused by overexpression of FAM83H and aberrant localization of CK-1a could contribute to the progression of colorectal cancer.

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Novel surface targets and serum biomarkers from the ovarian cancer vasculature

Cited by 39 publications

References 34 publications

ADAM12 Is a Novel Regulator of Tumor Angiogenesis via STAT3 Signaling

ADAM12 Is a Novel Regulator of Tumor Angiogenesis via STAT3 Signaling

T Cells Bearing a Chimeric Antigen Receptor against Prostate-Specific Membrane Antigen Mediate Vascular Disruption and Result in Tumor Regression

A novel mechanism of keratin cytoskeleton organization through casein kinase Iα and FAM83H in colorectal cancer

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