TY - JOUR
T1 - Macrophages induce "budding" in aggressive human colon cancer subtypes by protease-mediated disruption of tight junctions
AU - Trumpi, Kari
AU - Frenkel, Nicola
AU - Peters, Timo
AU - Korthagen, Nicoline M.
AU - Jongen, Jennifer M.J.
AU - Raats, Daniëlle
AU - van Grevenstein, Helma
AU - Backes, Yara
AU - Moons, Leon M.
AU - Lacle, Miangela M.
AU - Koster, Jan
AU - Zwijnenburg, Danny
AU - Rinkes, Inne H.M.Borel
AU - Kranenburg, Onno
PY - 2018/4/13
Y1 - 2018/4/13
N2 - Primary human colorectal tumors with a high stromal content have an increased capacity to metastasize. Cancer-associated fibroblasts (CAFs) promote metastasis, but the contribution of other stromal cell types is unclear. Here we searched for additional stromal cell types that contribute to aggressive tumor cell behavior. By making use of the 'immunome compendium'-a collection of gene signatures reflecting the presence of specific immune cell-types-we show that macrophage signatures are most strongly associated with a high CAF content and with poor prognosis in multiple large cohorts of primary tumors and liver metastases. Co-culturing macrophages with patientderived colonospheres promoted 'budding' of small clusters of tumor cells from the bulk. Immunohistochemistry showed that budding tumor clusters in stroma-rich areas of T1 colorectal carcinomas were surrounded by macrophages. In vitro budding was accompanied by reduced levels of the tight junction protein occludin, but OCLN mRNA levels did not change, nor did markers of epithelial mesenchymal transition. Budding was accompanied by nuclear accumulation of β-catenin, which was also observed in budding tumor cell clusters in situ. The NFκB inhibitor Sanguinarine resulted in a decrease in MMP7 protein expression and both NFκB inhibitor Sanguinarine and MMP inhibitor Batimastat prevented occludin degradation and budding. We conclude that macrophages contribute to the aggressive nature of stromarich colon tumors by promoting an MMP-dependent pathway that operates in parallel to classical EMT and leads to tight junction disruption.
AB - Primary human colorectal tumors with a high stromal content have an increased capacity to metastasize. Cancer-associated fibroblasts (CAFs) promote metastasis, but the contribution of other stromal cell types is unclear. Here we searched for additional stromal cell types that contribute to aggressive tumor cell behavior. By making use of the 'immunome compendium'-a collection of gene signatures reflecting the presence of specific immune cell-types-we show that macrophage signatures are most strongly associated with a high CAF content and with poor prognosis in multiple large cohorts of primary tumors and liver metastases. Co-culturing macrophages with patientderived colonospheres promoted 'budding' of small clusters of tumor cells from the bulk. Immunohistochemistry showed that budding tumor clusters in stroma-rich areas of T1 colorectal carcinomas were surrounded by macrophages. In vitro budding was accompanied by reduced levels of the tight junction protein occludin, but OCLN mRNA levels did not change, nor did markers of epithelial mesenchymal transition. Budding was accompanied by nuclear accumulation of β-catenin, which was also observed in budding tumor cell clusters in situ. The NFκB inhibitor Sanguinarine resulted in a decrease in MMP7 protein expression and both NFκB inhibitor Sanguinarine and MMP inhibitor Batimastat prevented occludin degradation and budding. We conclude that macrophages contribute to the aggressive nature of stromarich colon tumors by promoting an MMP-dependent pathway that operates in parallel to classical EMT and leads to tight junction disruption.
KW - Budding
KW - Colorectal
KW - Consensus molecular subtypes
KW - Matrix metalloprotease
KW - Metastasis
UR - http://www.scopus.com/inward/record.url?scp=85045331175&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.24626
DO - 10.18632/oncotarget.24626
M3 - Article
AN - SCOPUS:85045331175
SN - 1949-2553
VL - 9
SP - 19490
EP - 19507
JO - Oncotarget
JF - Oncotarget
IS - 28
ER -