TY - JOUR
T1 - Transcriptional activity of ATF3 in the stromal compartment of tumors promotes cancer progression
AU - Buganimy, Yosef
AU - Madary, Shalom
AU - Rais, Yoach
AU - Pomeraniec, Leslie
AU - Harel, Einav
AU - Solomon, Hilla
AU - Kalo, Eyal
AU - Goldstein, Ido
AU - Brosh, Ran
AU - Haimov, Ora
AU - Avivi, Camila
AU - Polak-Charcon, Sylvie
AU - Goldfinger, Naomi
AU - Barshack, Iris
AU - Rotter, Varda
N1 - Funding Information:
Center of Excellence grant from Flight Attendant Medical Research Institute, Yad Abraham Center for Cancer Diagnosis and Therapy and by European Community FP7-INFLACARE number-223151.
PY - 2011/12
Y1 - 2011/12
N2 - Compelling evidences have rendered the tumor microenvironment a crucial determinant in cancer outcome. Activating transcription factor 3 (ATF3), a stress response transcription factor, is known to have a dichotomous role in tumor cells, acting either as a tumor suppressor or an oncogene in a context-dependent manner. However, its expression and possible role in the tumor microenvironment are hitherto unknown. Here we show that ATF3 is upregulated in the stromal compartment of several types of cancer. Accordingly, Cancer-associated fibroblasts (CAFs) ectopically expressing ATF3 proliferated faster as indicated by increased colony-forming capacity and promoted the growth of adjacent tumor cells when co-injected into nude mice. Utilizing a genome-wide profiling approach, we unraveled a robust gene expression program induced by ATF3 in CAFs. Focusing on a specific subset of genes, we found that the ability of stromal ATF3 to promote cancer progression is mediated by transcriptional repression of CLDN1 and induction of CXCL12 and RGS4. In addition, regulation of LIF, CLDN1, SERPINE2, HSD17B2, ITGA7 and PODXL by ATF3 mediated the increased proliferation capacity of CAFs. In sum, our findings implicate ATF3 as a novel stromal tumor promoter and suggest that targeting ATF3 pathway might be beneficial for anticancer therapy.
AB - Compelling evidences have rendered the tumor microenvironment a crucial determinant in cancer outcome. Activating transcription factor 3 (ATF3), a stress response transcription factor, is known to have a dichotomous role in tumor cells, acting either as a tumor suppressor or an oncogene in a context-dependent manner. However, its expression and possible role in the tumor microenvironment are hitherto unknown. Here we show that ATF3 is upregulated in the stromal compartment of several types of cancer. Accordingly, Cancer-associated fibroblasts (CAFs) ectopically expressing ATF3 proliferated faster as indicated by increased colony-forming capacity and promoted the growth of adjacent tumor cells when co-injected into nude mice. Utilizing a genome-wide profiling approach, we unraveled a robust gene expression program induced by ATF3 in CAFs. Focusing on a specific subset of genes, we found that the ability of stromal ATF3 to promote cancer progression is mediated by transcriptional repression of CLDN1 and induction of CXCL12 and RGS4. In addition, regulation of LIF, CLDN1, SERPINE2, HSD17B2, ITGA7 and PODXL by ATF3 mediated the increased proliferation capacity of CAFs. In sum, our findings implicate ATF3 as a novel stromal tumor promoter and suggest that targeting ATF3 pathway might be beneficial for anticancer therapy.
UR - http://www.scopus.com/inward/record.url?scp=81855217391&partnerID=8YFLogxK
U2 - 10.1093/carcin/bgr203
DO - 10.1093/carcin/bgr203
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C2 - 21900211
AN - SCOPUS:81855217391
SN - 0143-3334
VL - 32
SP - 1749
EP - 1757
JO - Carcinogenesis
JF - Carcinogenesis
IS - 12
M1 - bgr203
ER -
