The cell-adhesion and signaling molecule PECAM-1 is a molecular mediator of resistance to genotoxic chemotherapy

Bergom, Carmen; Goel, Reema; Paddock, Cathy; Gao, Cunji; Newman, Debra K.; Matsuyama, Shigemi; Newman, Peter J.

doi:10.4161/cbt.5.12.3467

Cited by 27 publications

(32 citation statements)

References 49 publications

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“…5,6 A substantial literature has implicated the tumor microenvironment as a factor in resistance, 7,8,[9][10][11] with a particular role for cell adhesion proteins. 12,13 There is evidence for this in the case of doxorubicin and melphalan, 14 etoposide, 15 cyclophosphamide, 16 cisplatinum, 17,18 mitoxantrone, 19 vincristine 20 and Imatinib. 21 Previously, we used SAGE analysis to identify differences in gene expression patterns between cancers identified as intractable and those more tractable to chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

PolyHEMA spheroids are an inadequate model for the drug resistance of the intractable solid tumors

Steadman¹,

Stein²,

Litman³

et al. 2008

Cell Cycle

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Cancers arising in pancreas, lung, liver and stomach are difficult to treat successfully. Wanting to understand the basis for such intractability, we previously performed comparative analyses of publicly available gene expression data from tumor biopsies. Expression of many cell adhesion genes correlated significantly with intractability of cancers, our surrogate of intractability being the SEER five-year survivals of patients with disseminated tumors. To model resistance mediated by cell adhesion, we evaluated HCT 116 cells grown in two modes differing in cell adhesion status: (i) as monolayers attached to plastic culture dishes, (ii) cells attached to one another in spheroids. We determined gene expression profiles of cells grown in these two modes, for three or six days, using the human genome U133A microarray (Affymetrix, Inc.). There was a striking overlap between (a) the genes expressed differentially between early monolayers and early spheroids and (b) those expressed differentially between early and confluent monolayers. However, there was no similarity between these overlaps and the genes that were differentially expressed in intractable, as opposed to more tractable, tumors. We hypothesize that the cytotoxicity resistance for poly-HEMA spheroids and for confluent cells have a similar basis, one that differs from the resistance found in intractable solid tumors in patients. Cytotoxicity, cell cycle and immunohistochemistry assays on early and on confluent monolayers, and on spheroids, showed similarities between these latter two conditions. We conclude that while spheroids (and confluent monolayer cells) show drug resistance, the mechanisms underlying this resistance diverge from those conferring resistance to intractable cancers.

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Section: Introductionmentioning

confidence: 99%

PolyHEMA spheroids are an inadequate model for the drug resistance of the intractable solid tumors

Steadman¹,

Stein²,

Litman³

et al. 2008

Cell Cycle

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show abstract

“…expressed as a protein in human and murine tissues and, if so, whether it functions differently in its ability to protect cells from apoptosis -a property previously shown to require the PECAM-1 cytoplasmic domain (Bergom et al, 2006). We report herein a potential role for the C-terminal region of PECAM-1 in cytoprotective signaling that might have implications for the expression of different PECAM-1 isoforms during embryogenesis, development and the progression of cancer.…”

Section: Introductionmentioning

confidence: 92%

“…However, recent work has shown that, at least in certain systems, the PECAM-1-SHP-2 signaling complex might not fully account for the cytoprotective effects of PECAM-1 (Bergom et al, 2006). To determine whether the changes in the Δ15 cytoplasmic domain alter intracellular survival signals emanating from PECAM-1, we examined whether Δ15 PECAM-1 is able to protect cells efficiently against cell death induced by overexpression of Bax in a HEK293T cell model system (Gao et al, 2003).…”

Section: The δ15 Pecam-1 Isoform Contains Functional Itim Domains Andmentioning

confidence: 99%

“…At the physiological level, PECAM-1 protects against septic shock (Maas et al, 2005;Carrithers et al, 2005) and modulates reactive oxygen species produced by coronary microvessels (Liu et al, 2006). Recent studies also indicate that PECAM-1 can protect against cell death in a variety of systems, and its presence can influence a number of classical cell-survival pathways (Noble et al, 1999;Bird et al, 1999;Evans et al, 2001;Ferrero et al, 2003;Gao et al, 2003;Limaye et al, 2005;Bergom et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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An alternatively spliced isoform of PECAM-1 is expressed at high levels in human and murine tissues, and suggests a novel role for the C-terminus of PECAM-1 in cytoprotective signaling

Bergom

Paddock

Gao

et al. 2008

Journal of Cell Science

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histiocytic lymphoma cell lines. Furthermore, murine platelets and lung lysates demonstrated abundant amounts of exon-15-deficient PECAM-1. Functional studies revealed that Δ15 PECAM-1 retains both its homophilic binding capacity and its ability to signal by means of its immunoreceptor tyrosine-based inhibitory motif (ITIM) domains. Δ15 PECAM-1 was unable, however, to protect against apoptosis induced by overexpression of Bax or treatment with the chemotherapy agent etoposide. These studies suggest a novel role for the PECAM-1 C-terminus in cytoprotective signaling and highlight a need for further characterization of expression of PECAM-1 isoforms in normal and malignant tissues.

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“…In light of this, the report by Bergon and colleagues in the previous issue 21 is important because it suggests for PECAM-1-expressing tumors, 22 such as blood malignancies, that in addition to a potential impact on the tumor microenvironment, inhibition of PECAM-1 function or expression may also have direct effects on these tumors. Specifically, they report that expression of PECAM-1 on lymphoid malignancies confers resistance to apoptosis induced by chemotherapeutic agents and that lowering PECAM-1 on lymphoid tumors increases their susceptibility to chemotherapy-induced apoptosis.…”

mentioning

confidence: 99%

Targeting PECAM-1 for anti-cancer therapy

DeLisser

2007

Cancer Biology & Therapy

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The cell-adhesion and signaling molecule PECAM-1 is a molecular mediator of resistance to genotoxic chemotherapy

Cited by 27 publications

References 49 publications

PolyHEMA spheroids are an inadequate model for the drug resistance of the intractable solid tumors

PolyHEMA spheroids are an inadequate model for the drug resistance of the intractable solid tumors

An alternatively spliced isoform of PECAM-1 is expressed at high levels in human and murine tissues, and suggests a novel role for the C-terminus of PECAM-1 in cytoprotective signaling

Targeting PECAM-1 for anti-cancer therapy

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