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Abrogation of junctional adhesion molecule-A expression induces cell apoptosis and reduces breast cancer progression.

Murakami M, Giampietro C, Giannotta M, Corada M, Torselli I, Orsenigo F, Cocito A, d'Ario G, Mazzarol G, Confalonieri S, Di Fiore PP, Dejana E - PLoS ONE (2011)

Bottom Line: Angiogenesis and inflammatory or immune infiltrate were not statistically modified in absence of JAM-A but tumor cell apoptosis was significantly increased.We conclude that down regulation of JAM-A reduces tumor aggressive behavior by increasing cell susceptibility to apoptosis.JAM-A may be considered a negative prognostic factor and a potential therapeutic target.

View Article: PubMed Central - PubMed

Affiliation: IFOM, Foundation FIRC Institute of Molecular Oncology, Milan, Italy.

ABSTRACT
Intercellular junctions promote homotypic cell to cell adhesion and transfer intracellular signals which control cell growth and apoptosis. Junctional adhesion molecule-A (JAM-A) is a transmembrane immunoglobulin located at tight junctions of normal epithelial cells of mammary ducts and glands. In the present paper we show that JAM-A acts as a survival factor for mammary carcinoma cells. JAM-A mice expressing Polyoma Middle T under MMTV promoter develop significantly smaller mammary tumors than JAM-A positive mice. Angiogenesis and inflammatory or immune infiltrate were not statistically modified in absence of JAM-A but tumor cell apoptosis was significantly increased. Tumor cells isolated from JAM-A mice or 4T1 cells incubated with JAM-A blocking antibodies showed reduced growth and increased apoptosis which paralleled altered junctional architecture and adhesive function. In a breast cancer clinical data set, tissue microarray data show that JAM-A expression correlates with poor prognosis. Gene expression analysis of mouse tumor samples showed a correlation between genes enriched in human G3 tumors and genes over expressed in JAM-A +/+ mammary tumors. Conversely, genes enriched in G1 human tumors correlate with genes overexpressed in JAM-A-/- tumors. We conclude that down regulation of JAM-A reduces tumor aggressive behavior by increasing cell susceptibility to apoptosis. JAM-A may be considered a negative prognostic factor and a potential therapeutic target.

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Abrogation of JAM-A expression increases tumor cell apoptosis.A) Histological examination shows lower cell proliferation and higher apoptosis in MMTV-PyVmT/JAM-A−/− as compared to JAM-A+/+ tumors. Right panels show quantification of Ki-67 or TUNEL positive cells. Data are means +/− SEM *p<0.05 by unpaired Student's t test. Scale bar: 100 µm. B) The growth curve of 4T1 cells in the presence of a control (Ctrl) antibody (Ab) or a JAM-A neutralizing Ab (BV11) was measured in the presence (left upper panel) or absence of fetal bovine serum (FBS) (left lower panel). Under starving conditions, upon exposure to a JAM-A blocking Ab the total cell number was significantly reduced while the number of TUNEL-positive cells was increased. Values are means ± SEM of at least 4 replicates from 3 independent experiments. *p<0.05, **p<0.01 by unpaired Student-t test.
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pone-0021242-g002: Abrogation of JAM-A expression increases tumor cell apoptosis.A) Histological examination shows lower cell proliferation and higher apoptosis in MMTV-PyVmT/JAM-A−/− as compared to JAM-A+/+ tumors. Right panels show quantification of Ki-67 or TUNEL positive cells. Data are means +/− SEM *p<0.05 by unpaired Student's t test. Scale bar: 100 µm. B) The growth curve of 4T1 cells in the presence of a control (Ctrl) antibody (Ab) or a JAM-A neutralizing Ab (BV11) was measured in the presence (left upper panel) or absence of fetal bovine serum (FBS) (left lower panel). Under starving conditions, upon exposure to a JAM-A blocking Ab the total cell number was significantly reduced while the number of TUNEL-positive cells was increased. Values are means ± SEM of at least 4 replicates from 3 independent experiments. *p<0.05, **p<0.01 by unpaired Student-t test.

Mentions: JAM-A is expressed in mammary tumor vasculature (Figure S1). We have previously shown that the absence of JAM-A reduced Rip1Tag2 pancreatic islet tumor size, angiogenesis and inflammatory infiltrate [9]. Analysis of MMTV-PyVmT tumors showed that in absence of JAM-A, tumor cells proliferate slightly less (27.73±2.29% versus 35.6±2.02, p<0.05) but undergo apoptosis to higher extent than in the presence of this adhesive molecule (96.4±10.2 versus 63.1±8.5 cells per mm2 p<0.05) (Fig. 2A). Conversely, no statistically significant difference in tumor angiogenesis (Figure S3A), inflammatory (F4/80 positive cells, Figure S3B) and immune cell infiltrate (CD11c and MHCII positive cells) was observed (Figure S3C). The number of CD4+ and CD8+ lymphocytes was increased in the tumors but the difference did not reach statistical significance.


Abrogation of junctional adhesion molecule-A expression induces cell apoptosis and reduces breast cancer progression.

Murakami M, Giampietro C, Giannotta M, Corada M, Torselli I, Orsenigo F, Cocito A, d'Ario G, Mazzarol G, Confalonieri S, Di Fiore PP, Dejana E - PLoS ONE (2011)

Abrogation of JAM-A expression increases tumor cell apoptosis.A) Histological examination shows lower cell proliferation and higher apoptosis in MMTV-PyVmT/JAM-A−/− as compared to JAM-A+/+ tumors. Right panels show quantification of Ki-67 or TUNEL positive cells. Data are means +/− SEM *p<0.05 by unpaired Student's t test. Scale bar: 100 µm. B) The growth curve of 4T1 cells in the presence of a control (Ctrl) antibody (Ab) or a JAM-A neutralizing Ab (BV11) was measured in the presence (left upper panel) or absence of fetal bovine serum (FBS) (left lower panel). Under starving conditions, upon exposure to a JAM-A blocking Ab the total cell number was significantly reduced while the number of TUNEL-positive cells was increased. Values are means ± SEM of at least 4 replicates from 3 independent experiments. *p<0.05, **p<0.01 by unpaired Student-t test.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3117883&req=5

pone-0021242-g002: Abrogation of JAM-A expression increases tumor cell apoptosis.A) Histological examination shows lower cell proliferation and higher apoptosis in MMTV-PyVmT/JAM-A−/− as compared to JAM-A+/+ tumors. Right panels show quantification of Ki-67 or TUNEL positive cells. Data are means +/− SEM *p<0.05 by unpaired Student's t test. Scale bar: 100 µm. B) The growth curve of 4T1 cells in the presence of a control (Ctrl) antibody (Ab) or a JAM-A neutralizing Ab (BV11) was measured in the presence (left upper panel) or absence of fetal bovine serum (FBS) (left lower panel). Under starving conditions, upon exposure to a JAM-A blocking Ab the total cell number was significantly reduced while the number of TUNEL-positive cells was increased. Values are means ± SEM of at least 4 replicates from 3 independent experiments. *p<0.05, **p<0.01 by unpaired Student-t test.
Mentions: JAM-A is expressed in mammary tumor vasculature (Figure S1). We have previously shown that the absence of JAM-A reduced Rip1Tag2 pancreatic islet tumor size, angiogenesis and inflammatory infiltrate [9]. Analysis of MMTV-PyVmT tumors showed that in absence of JAM-A, tumor cells proliferate slightly less (27.73±2.29% versus 35.6±2.02, p<0.05) but undergo apoptosis to higher extent than in the presence of this adhesive molecule (96.4±10.2 versus 63.1±8.5 cells per mm2 p<0.05) (Fig. 2A). Conversely, no statistically significant difference in tumor angiogenesis (Figure S3A), inflammatory (F4/80 positive cells, Figure S3B) and immune cell infiltrate (CD11c and MHCII positive cells) was observed (Figure S3C). The number of CD4+ and CD8+ lymphocytes was increased in the tumors but the difference did not reach statistical significance.

Bottom Line: Angiogenesis and inflammatory or immune infiltrate were not statistically modified in absence of JAM-A but tumor cell apoptosis was significantly increased.We conclude that down regulation of JAM-A reduces tumor aggressive behavior by increasing cell susceptibility to apoptosis.JAM-A may be considered a negative prognostic factor and a potential therapeutic target.

View Article: PubMed Central - PubMed

Affiliation: IFOM, Foundation FIRC Institute of Molecular Oncology, Milan, Italy.

ABSTRACT
Intercellular junctions promote homotypic cell to cell adhesion and transfer intracellular signals which control cell growth and apoptosis. Junctional adhesion molecule-A (JAM-A) is a transmembrane immunoglobulin located at tight junctions of normal epithelial cells of mammary ducts and glands. In the present paper we show that JAM-A acts as a survival factor for mammary carcinoma cells. JAM-A mice expressing Polyoma Middle T under MMTV promoter develop significantly smaller mammary tumors than JAM-A positive mice. Angiogenesis and inflammatory or immune infiltrate were not statistically modified in absence of JAM-A but tumor cell apoptosis was significantly increased. Tumor cells isolated from JAM-A mice or 4T1 cells incubated with JAM-A blocking antibodies showed reduced growth and increased apoptosis which paralleled altered junctional architecture and adhesive function. In a breast cancer clinical data set, tissue microarray data show that JAM-A expression correlates with poor prognosis. Gene expression analysis of mouse tumor samples showed a correlation between genes enriched in human G3 tumors and genes over expressed in JAM-A +/+ mammary tumors. Conversely, genes enriched in G1 human tumors correlate with genes overexpressed in JAM-A-/- tumors. We conclude that down regulation of JAM-A reduces tumor aggressive behavior by increasing cell susceptibility to apoptosis. JAM-A may be considered a negative prognostic factor and a potential therapeutic target.

Show MeSH
Related in: MedlinePlus