TY - JOUR
T1 - Protumor steering of cancer inflammation by p50 nf-kb enhances colorectal cancer progression
AU - Porta, Chiara
AU - Ippolito, Alessandro
AU - Consonni, Francesca Maria
AU - Carraro, Lorenzo
AU - Celesti, Giuseppe
AU - Correale, Carmen
AU - Grizzi, Fabio
AU - Pasqualini, Fabio
AU - Tartari, Silvia
AU - Rinaldi, Maurizio
AU - Bianchi, Paolo
AU - Balzac, Fiorella
AU - Vetrano, Stefania
AU - Turco, Emilia
AU - Hirsch, Emilio
AU - Laghi, Luigi
AU - Sica, Antonio
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/5
Y1 - 2018/5
N2 - Although tumor-associated macrophages (TAM) display a M2-skewed tumor-promoting phenotype in most cancers, in colorectal cancer, both TAM polarization and its impact remain controversial. We investigated the role of the M2-polarizing p50 NF-kB subunit in orchestrating TAM phenotype, tumor microenvironment composition, and colorectal cancer progression. We first demonstrated, by parallel studies in colitis-associated cancer (CAC) and in genetically driven Apc Min mouse models, that the p50-dependent inhibition of M1-polarized gut inflammation supported colorectal cancer development. In accordance with these studies, p50 – / – mice displayed exacerbated CAC with fewer and smaller tumors, along with enhanced levels of M1/Th1 cytokines/chemokines, including IL12 and CXCL10, whose administration restrained CAC development in vivo. The inflammatory profile supporting tumor resistance in colons from p50 – /–tumor bearers correlated inversely with TAM load and positively with both recruitment of NK, NKT, CD8 þ T cells and number of apoptotic tumor cells. In agreement, myeloid-specific ablation of p50 promoted tumor resistance in mice, whereas in colorectal cancer patients, a high number of p50 þ TAMs at the invasive margin was associated with decreased IL12A and TBX21 expression and worse postsurgical outcome. Our findings point to p50 involvement in colorectal cancer development, through its engagement in the protumor activation of macrophages, and identify a candidate for prognostic and target therapeutic intervention.
AB - Although tumor-associated macrophages (TAM) display a M2-skewed tumor-promoting phenotype in most cancers, in colorectal cancer, both TAM polarization and its impact remain controversial. We investigated the role of the M2-polarizing p50 NF-kB subunit in orchestrating TAM phenotype, tumor microenvironment composition, and colorectal cancer progression. We first demonstrated, by parallel studies in colitis-associated cancer (CAC) and in genetically driven Apc Min mouse models, that the p50-dependent inhibition of M1-polarized gut inflammation supported colorectal cancer development. In accordance with these studies, p50 – / – mice displayed exacerbated CAC with fewer and smaller tumors, along with enhanced levels of M1/Th1 cytokines/chemokines, including IL12 and CXCL10, whose administration restrained CAC development in vivo. The inflammatory profile supporting tumor resistance in colons from p50 – /–tumor bearers correlated inversely with TAM load and positively with both recruitment of NK, NKT, CD8 þ T cells and number of apoptotic tumor cells. In agreement, myeloid-specific ablation of p50 promoted tumor resistance in mice, whereas in colorectal cancer patients, a high number of p50 þ TAMs at the invasive margin was associated with decreased IL12A and TBX21 expression and worse postsurgical outcome. Our findings point to p50 involvement in colorectal cancer development, through its engagement in the protumor activation of macrophages, and identify a candidate for prognostic and target therapeutic intervention.
UR - http://www.scopus.com/inward/record.url?scp=85047762465&partnerID=8YFLogxK
U2 - 10.1158/2326-6066.CIR-17-0036
DO - 10.1158/2326-6066.CIR-17-0036
M3 - Article
SN - 2326-6066
VL - 6
SP - 578
EP - 593
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 5
ER -