Systemic Analysis of Gene Expression Profiles Identifies ErbB3 as a Potential Drug Target in Pediatric Alveolar Rhabdomyosarcoma

Peer reviewe

Persistence of Bartonella spp. stealth pathogens : from sub-clinical infections to vasoproliferative tumour formation

Bartonella spp. are facultative intracellular bacteria that typically cause a long-lasting intraerythrocytic bacteremia in their mammalian reservoir hosts, thereby favoring transmission by blood-sucking arthropods. In most cases, natural reservoir host infections are subclinical and the relapsing intraerythrocytic bacteremia may last weeks, months or even years. In this review, we will follow the infection cycle of Bartonella spp. in a reservoir host, which typically starts with an intradermal inoculation of bacteria that are superficially scratched into the skin from arthropod feces and terminates with the pathogen exit by the blood-sucking arthropod. The current knowledge of bacterial countermeasures against mammalian immune response will be presented for each critical step of the pathogenesis. The prevailing models of the still-enigmatic primary niche, the anatomical location where bacteria reside, persist and are periodically seeded into the bloodstream to cause the typical relapsing Bartonella spp. bacteremia will also be critically discussed. The review will end up with a discussion of the ability of Bartonella spp., namely Bartonella henselae, Bartonella quintana and Bartonella bacilliformis, to induce tumor-like vascular deformations in humans having compromised immune response such as in AIDS patients

Expression profile of <i>VEGFC</i> in pediatric healthy and cancer tissues.

<p><b>A</b>) Body-wide expression profile of the <i>VEGFC</i> gene across the database. Each dot represents the expression of <i>VEGFC</i> in one sample. Anatomical origins of each sample are marked in color bars below the gene plot. The <i>VEGFC</i> gene is highly expressed in samples originating from malignant connective or muscular tissue (green dots). The ten green dots forming a separate group with high <i>VEGFC</i> expression all represent samples from Ewing’s sarcoma. <b>B</b>) Box plot analysis of the <i>VEGFC</i> gene expression levels across a variety of pediatric cancer samples. <i>VEGFC</i> is particularly highly expressed in Ewing’s sarcoma. NOS, not otherwise specified.</p

Expression profile of <i>ERBB3</i> in pediatric healthy and cancer tissues.

<p><b>A</b>) Body-wide expression profile of the <i>ERBB3</i> gene across the database. Each dot represents the expression of <i>ERBB3</i> in one sample. Anatomical origins of each sample are marked in color bars below the gene plot. The <i>ERBB3</i> gene is highly expressed in malignant connective and muscular tissue samples (green dots). <b>B</b>) Box plot analysis of the <i>ERBB3</i> gene expression levels across a variety of pediatric cancer samples. <i>ERBB3</i> is particularly highly expressed in alveolar rhabdomyosarcomas. NOS, not otherwise specified.</p

Hierarchial clustering of validated therapeutic target genes in rhabdomyosarcomas and Ewing’s sarcomas.

<p>The red boxes illustrate mRNA expression levels exceeding the mean expression per gene in the analyzed tissues, whereas the blue boxes illustrate mRNA expression levels lower than the mean expression per gene. The number of samples analyzed per tissue type is given in parentheses.</p

Expression and function of ErbB3 in rhabdomyosarcoma.

<p>(<b>A</b>) Western analysis of ErbB3 expression in RD cells transfected or not with a plasmid encoding ErbB3 or an empty vector control (lanes 1–3), or with <i>ERBB3</i>-targeting or control siRNA (lanes 4–5). Membranes were reblotted with anti-actin to control loading. (<b>B–D</b>) Immunohistochemical analysis of ErbB3 expression in normal adult human stomach (<b>B</b>) and in two samples representing pediatric alveolar rhabdomyosarcoma (<b>C</b>,<b>D</b>). (<b>E</b>,<b>F</b>) MTT proliferation analysis of the effect of <i>ERBB3</i> overexpression (<b>E</b>) or siRNA-mediated <i>ERBB3</i> down-regulation on the growth of RD cell transfectants. Expression of ErbB3 in the transfectants is shown in (<b>A</b>). *, <i>P</i><0.001 when compared to control. Scale bar in (<b>B–D</b>), 100 µm.</p

Expression profile of <i>EPHA2</i> in pediatric healthy and cancer tissues. A

<p>) Body-wide expression profile of the <i>EPHA2</i> gene across the database. Each dot represents the expression of <i>EPHA2</i> in one sample. Anatomical origins of each sample are marked in color bars below the gene plot. The <i>EPHA2</i> gene is highly expressed in malignant connective and muscular tissue samples (green dots). <b>B</b>) Box plot analysis of the <i>EPHA2</i> gene expression levels across a variety of pediatric cancer samples. <i>EPHA2</i> is particularly highly expressed in osteosarcoma and Ewing’s sarcoma. NOS, not otherwise specified.</p