Protumorigenic effects of Snail-expression fibroblasts on colon cancer cells.
Snail1 is a transcriptional factor that plays an important role in epithelial-mesenchymal transition and in the acquisition of invasive properties by epithelial cells. In colon tumors, Snail1 expression in the stroma correlates with lower specific survival of cancer patients. However, the role(s) of Snail1 expression in stroma and its association with patients' survival have not been determined. We used human primary carcinoma-associated fibroblasts (CAFs) or normal fibroblasts (NFs) and fibroblast cell lines to analyze the effects of Snail1 expression on the protumorigenic capabilities in colon cancer cells. Snail1 expression was higher in CAFs than in NFs and, as well as α-SMA, a classic marker of activated CAFs. Moreover, in tumor samples from 50 colon cancer patients, SNAI1 expression was associated with expression of other CAF markers, such as α-SMA and fibroblast activation protein. Interestingly, coculture of CAFs with colon cells induced a significant increase in epithelial cell migration and proliferation, which was associated with endogenous SNAI1 expression levels. Ectopic manipulation of Snail1 in fibroblasts demonstrated that Snail1 expression controlled migration as well as proliferation of cocultured colon cancer cells in a paracrine manner. Furthermore, expression of Snail1 in fibroblasts was required for the coadjuvant effect of these cells on colon cancer cell growth and invasion when coxenografted in nude mice. Finally, cytokine profile changes, particularly MCP-3 expression, in fibroblasts are put forward as mediators of Snail1-derived effects on colon tumor cell migration. In summary, these studies demonstrate that Snail1 is necessary for the protumorigenic effects of fibroblasts on colon cancer cells.
Department of Medical Oncology, Hospital Universitario Puerta de Hierro de Majadahonda, Majadahonda, Madrid, Spain.
Alberto
A
Herrera
Mercedes
M
Herrera
Lorena
L
Alba-Castellón
Javier
J
Silva
Vanesa
V
García
Jordina
J
Loubat-Casanovas
Ana
A
Alvarez-Cienfuegos
José
J
Miguel García
Rufo
R
Rodriguez
Beatriz
B
Gil
Ma Jesús Citores
Ma Jesús Larriba
J
J
Ignacio Casal
Antonio García
AG
de Herreros
Félix
F
Bonilla
Cristina
C
Peña
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D063646:Carcinogenesis; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D010450:Endopeptidases; D005260:Female; D005347:Fibroblasts / Q000473:pathology; D018093:Gelatinases / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000096:biosynthesis; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000099167:Fibroblast Activation Protein Alpha
D000199:Actins; D016207:Cytokines; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D012333:RNA, Messenger; D012697:Serine Endopeptidases; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D000099167:Fibroblast Activation Protein Alpha; C541116:ACTA2 protein, human; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse
Snail1; cancer-associated fibroblasts; cell migration; cell proliferation; colon cancer