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Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform.

Casazza A, Kigel B, Maione F, Capparuccia L, Kessler O, Giraudo E, Mazzone M, Neufeld G, Tamagnone L - EMBO Mol Med (2012)

Bottom Line: Here, we show that a mutated, uncleavable variant of Sema3E (Uncl-Sema3E) binds to PlexinD1 like p61-Sema3E, but does not promote the association of PlexinD1 with ErbB2 nor activates the ensuing signalling cascade leading to metastatic spreading.It activates a PlexinD1-mediated signalling cascade in endothelial cells that leads to the inhibition of adhesion to extracellular matrix, directional migration and cell survival.In summary, we conclude that Uncl-Sema3E is a novel inhibitor of tumour angiogenesis and growth that concomitantly hampers metastatic spreading.

View Article: PubMed Central - PubMed

Affiliation: Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, Candiolo, Italy.

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Systemic delivery of purified Uncl-Sema3E suppresses tumour growth and prevents metastatic spreadingA-C. 4T1 cancer cell were orthotopically transplanted into the mammary fat pad of nude mice. Four days after transplant, mice bearing palpable tumours were randomized and divided into two groups (n = 8, each group); control group was treated with 30 mg/kg of purified Uncl-Sema3E, while the other was treated with the same concentration of bovine albumin (mock negative control). The treatment with purified Uncl-Sema3E impaired the growth of orthotopic tumours (A and B) and the formation of spontaneous lung metastasis (C).
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fig10: Systemic delivery of purified Uncl-Sema3E suppresses tumour growth and prevents metastatic spreadingA-C. 4T1 cancer cell were orthotopically transplanted into the mammary fat pad of nude mice. Four days after transplant, mice bearing palpable tumours were randomized and divided into two groups (n = 8, each group); control group was treated with 30 mg/kg of purified Uncl-Sema3E, while the other was treated with the same concentration of bovine albumin (mock negative control). The treatment with purified Uncl-Sema3E impaired the growth of orthotopic tumours (A and B) and the formation of spontaneous lung metastasis (C).

Mentions: Finally, we tested the therapeutic efficacy of affinity-purified Uncl-Sema3E molecule administered systemically to tumour-bearing mice. Mice were transplanted orthotopically with 4T1 highly metastatic tumour cells and, as soon as developing palpable tumours (4–5 days after transplantation), they were treated i.p. with 30 mg/kg of purified Uncl-Sema3E three times/week for 18 days; the same amount of albumin was administered in control mice. Importantly, blood counts as well as liver and kidney markers were not altered in tumour-bearing mice treated with Uncl-Sema3E compared to controls (Supporting Information Fig 13A). Moreover, experiments performed in young healthy mice revealed that the systemic delivery of Uncl-Sema3E did not interfere with body growth or mouse behaviour (Supporting Information Fig 13B and unpublished observations), further suggesting that this treatment does not produce major adverse side effects. The systemic delivery of purified Uncl-Sema3E strikingly inhibited tumour growth (Fig 10A and B). Moreover, this treatment efficiently reduced metastasis formation (Fig 10C). Notably, Uncl-Sema3E inhibited tumour growth in vivo independently from PlexinD1 expression in cancer cells, as demonstrated by gene knock down experiments (Supporting Information Fig 14). This indicates that the activity of Uncl-Sema3E in the microenvironment is pivotal for the inhibition of tumour growth. Notably, primary tumours formed by PlexinD1-depleted cells are basally less metastatic due to the impairment of autocrine p61 signalling (Casazza et al, 2010); thus, the dominant-negative anti-metastatic effect of Uncl-Sema3E cannot be seen in tumours lacking expression of the implicated receptor PlexinD1 in cancer cells. In sum, either the removal of PlexinD1 receptor in tumour cells or the systemic delivery of the p61-competing molecule Uncl-Sema3E similarly achieved a significant reduction of the metastatic spreading in vivo.


Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform.

Casazza A, Kigel B, Maione F, Capparuccia L, Kessler O, Giraudo E, Mazzone M, Neufeld G, Tamagnone L - EMBO Mol Med (2012)

Systemic delivery of purified Uncl-Sema3E suppresses tumour growth and prevents metastatic spreadingA-C. 4T1 cancer cell were orthotopically transplanted into the mammary fat pad of nude mice. Four days after transplant, mice bearing palpable tumours were randomized and divided into two groups (n = 8, each group); control group was treated with 30 mg/kg of purified Uncl-Sema3E, while the other was treated with the same concentration of bovine albumin (mock negative control). The treatment with purified Uncl-Sema3E impaired the growth of orthotopic tumours (A and B) and the formation of spontaneous lung metastasis (C).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3376853&req=5

fig10: Systemic delivery of purified Uncl-Sema3E suppresses tumour growth and prevents metastatic spreadingA-C. 4T1 cancer cell were orthotopically transplanted into the mammary fat pad of nude mice. Four days after transplant, mice bearing palpable tumours were randomized and divided into two groups (n = 8, each group); control group was treated with 30 mg/kg of purified Uncl-Sema3E, while the other was treated with the same concentration of bovine albumin (mock negative control). The treatment with purified Uncl-Sema3E impaired the growth of orthotopic tumours (A and B) and the formation of spontaneous lung metastasis (C).
Mentions: Finally, we tested the therapeutic efficacy of affinity-purified Uncl-Sema3E molecule administered systemically to tumour-bearing mice. Mice were transplanted orthotopically with 4T1 highly metastatic tumour cells and, as soon as developing palpable tumours (4–5 days after transplantation), they were treated i.p. with 30 mg/kg of purified Uncl-Sema3E three times/week for 18 days; the same amount of albumin was administered in control mice. Importantly, blood counts as well as liver and kidney markers were not altered in tumour-bearing mice treated with Uncl-Sema3E compared to controls (Supporting Information Fig 13A). Moreover, experiments performed in young healthy mice revealed that the systemic delivery of Uncl-Sema3E did not interfere with body growth or mouse behaviour (Supporting Information Fig 13B and unpublished observations), further suggesting that this treatment does not produce major adverse side effects. The systemic delivery of purified Uncl-Sema3E strikingly inhibited tumour growth (Fig 10A and B). Moreover, this treatment efficiently reduced metastasis formation (Fig 10C). Notably, Uncl-Sema3E inhibited tumour growth in vivo independently from PlexinD1 expression in cancer cells, as demonstrated by gene knock down experiments (Supporting Information Fig 14). This indicates that the activity of Uncl-Sema3E in the microenvironment is pivotal for the inhibition of tumour growth. Notably, primary tumours formed by PlexinD1-depleted cells are basally less metastatic due to the impairment of autocrine p61 signalling (Casazza et al, 2010); thus, the dominant-negative anti-metastatic effect of Uncl-Sema3E cannot be seen in tumours lacking expression of the implicated receptor PlexinD1 in cancer cells. In sum, either the removal of PlexinD1 receptor in tumour cells or the systemic delivery of the p61-competing molecule Uncl-Sema3E similarly achieved a significant reduction of the metastatic spreading in vivo.

Bottom Line: Here, we show that a mutated, uncleavable variant of Sema3E (Uncl-Sema3E) binds to PlexinD1 like p61-Sema3E, but does not promote the association of PlexinD1 with ErbB2 nor activates the ensuing signalling cascade leading to metastatic spreading.It activates a PlexinD1-mediated signalling cascade in endothelial cells that leads to the inhibition of adhesion to extracellular matrix, directional migration and cell survival.In summary, we conclude that Uncl-Sema3E is a novel inhibitor of tumour angiogenesis and growth that concomitantly hampers metastatic spreading.

View Article: PubMed Central - PubMed

Affiliation: Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, Candiolo, Italy.

Show MeSH
Related in: MedlinePlus