TY - JOUR
T1 - Crosstalk between stromal components and tumor cells of TNBC via secreted factors enhances tumor growth and metastasis
AU - Jin, Kideok
AU - Pandey, Niranjan B.
AU - Popel, Aleksander S.
N1 - Funding Information:
We thank ACEA Biosciences and Dr. Yama Abassi for technical advice for using RTCA system. This work was supported by the National Institutes of Health grant R01 CA138264.
Publisher Copyright:
© Jin et al.
PY - 2017
Y1 - 2017
N2 - Triple negative breast cancer (TNBC) as a metastatic disease is currently incurable. Reliable and reproducible methods for testing drugs against metastasis are not available. Stromal cells may play a critical role in tumor progression and metastasis. In this study, we determined that fibroblasts and macrophages secreted IL-8 upon induction by tumor cell-conditioned media (TCM) from MDA-MB-231 cancer cells. Our data showed that the proliferation of MDA-MB-231 cells co-cultured with fibroblasts or macrophages was enhanced compared to the monoculture. Furthermore, TNBC cell migration, a key step in tumor metastasis, was promoted by conditioned media (CM) from TCM-induced fibroblasts or macrophages. Knockdown of the IL-8 receptor CXCR2 by CRISPR-Cas9 reduces MDA-MB-231 cell proliferation and migration compared to wild type. In a mouse xenograft tumor model, the growth of MDA-MB- 231-CXCR2-/- tumor was significantly decreased compared to the growth of tumors from wild-type cells. In addition, the incidence of thoracic metastasis of MDA-MB-231- CXCR2-/- tumors was reduced compared to wild type. We found that the auto- and paracrine loop exists between TNBC cells and stroma, which results in enhanced IL-8 secretion from the stromal components. Significantly, inhibition of the IL-8 signaling pathway by reparixin, an inhibitor of the IL-8 receptor, CXCR1/2, reduced MDAMB- 231 tumor growth and metastasis. Taken together, these findings implicate IL-8 signaling as a critical event in TNBC tumor growth and metastasis via crosstalk with stromal components.
AB - Triple negative breast cancer (TNBC) as a metastatic disease is currently incurable. Reliable and reproducible methods for testing drugs against metastasis are not available. Stromal cells may play a critical role in tumor progression and metastasis. In this study, we determined that fibroblasts and macrophages secreted IL-8 upon induction by tumor cell-conditioned media (TCM) from MDA-MB-231 cancer cells. Our data showed that the proliferation of MDA-MB-231 cells co-cultured with fibroblasts or macrophages was enhanced compared to the monoculture. Furthermore, TNBC cell migration, a key step in tumor metastasis, was promoted by conditioned media (CM) from TCM-induced fibroblasts or macrophages. Knockdown of the IL-8 receptor CXCR2 by CRISPR-Cas9 reduces MDA-MB-231 cell proliferation and migration compared to wild type. In a mouse xenograft tumor model, the growth of MDA-MB- 231-CXCR2-/- tumor was significantly decreased compared to the growth of tumors from wild-type cells. In addition, the incidence of thoracic metastasis of MDA-MB-231- CXCR2-/- tumors was reduced compared to wild type. We found that the auto- and paracrine loop exists between TNBC cells and stroma, which results in enhanced IL-8 secretion from the stromal components. Significantly, inhibition of the IL-8 signaling pathway by reparixin, an inhibitor of the IL-8 receptor, CXCR1/2, reduced MDAMB- 231 tumor growth and metastasis. Taken together, these findings implicate IL-8 signaling as a critical event in TNBC tumor growth and metastasis via crosstalk with stromal components.
KW - Breast cancer
KW - CXCR1/2
KW - IL-8
KW - TNBC
KW - Tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85030468040&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85030468040&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.19417
DO - 10.18632/oncotarget.19417
M3 - Article
C2 - 28947965
AN - SCOPUS:85030468040
SN - 1949-2553
VL - 8
SP - 60210
EP - 60222
JO - Oncotarget
JF - Oncotarget
IS - 36
ER -