Proteolytic processing converts the repelling signal Sema3E into an inducer of invasive growth and lung metastasis

Luca Tamagnone, Claus Christensen, Noona Ambartsumian, Giorgio Gilestro, Birthe Thomsen, Paolo Comoglio, Per Guldberg, Eugene Lukanidin

Risultato della ricerca: Contributo in rivistaArticolo in rivista

93 Citazioni (Scopus)

Abstract

We have previously shown that the expression of a semaphorin, known as a repelling cue in axon guidance, Sema3E, correlates with the ability to form lung metastasis in murine adenocarcinoma cell models. Now, besides providing evidence for the relevance of SEMA3E to human disease by showing that SEMA3E is frequently expressed in human cancer cell lines and solid tumors from breast cancer patients, we show biological activities of Sema3E, which support the implication of Sema3E in tumor progression and metastasis. In vivo, expression of Sema3E in mammary adenocarcinoma cells induces the ability to form experimental lung metastasis, and in vitro, the Sema3E protein exhibits both migration and growth promoting activity on endothelial cells and pheochromocytoma cells. This represents the first evidence of a metastasis-promoting function of a class 3 semaphorin, as this class of genes has hitherto been implicated in tumor biology only as tumor suppressors and negative regulators of growth. Moreover, we show that the full-size Sema3E protein is converted into a p61-Sema3E isoform due to furin-dependent processing, and by analyzing processing-deficient and truncated forms, we show that the generation of p61-Sema3E is required and sufficient for the function of Sema3E in lung metastasis, cell migration, invasive growth, and extracellular signal-regulated kinase 1/2 activation of endothelial cells. These findings suggest that certain breast cancer cells may increase their lung-colonizing ability by converting the growth repellent, Sema3E, into a growth attractant and point to a type of semaphorin signaling different from the conventional signaling induced by full-size dimeric class 3 semaphorins. ©2005 American Association for Cancer Research.
Lingua originaleEnglish
pagine (da-a)6167-6177
Numero di pagine11
RivistaCancer Research
Volume65
DOI
Stato di pubblicazionePubblicato - 2005

Keywords

  • Adenocarcinoma
  • Amino Acid Sequence
  • Animals
  • Breast Neoplasms
  • COS Cells
  • Cancer Research
  • Cell Line, Tumor
  • Cell Movement
  • Cercopithecus aethiops
  • Disease Models, Animal
  • Female
  • Furin
  • Humans
  • Lung Neoplasms
  • Mice
  • Mice, Inbred BALB C
  • Molecular Sequence Data
  • Neoplasm Invasiveness
  • Neurites
  • Oncology
  • PC12 Cells
  • Protein Isoforms
  • Rats
  • Semaphorins

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