Figure 1. Breast cancer survival
Chemotherapy results in a burst of paracrine factors near breast tumors that
upregulate survival pathways in the cancer cells, causing chemotherapeutic
resistance and metastasis. The process begins when chemotherapy induces the
release of tumor necrosis factor-a (TNF-a) [a] from stromal cells
in the breast, including endothelial cells. As a result, chemokine CXC motif ligand 1
(CXCL1; GRO; MGSA) and CXCL2 (MIP2) are upregulated
in breast cancer cells [b] by mechanisms including TNF-a release. The release
of CXCL1 and CXCL2 attracts CXC chemokine receptor 2
stromal cells from the tumor microenvironment to the tumor. Specifically,
CXCR2-expressing, complement receptor 3
(CR3; CD11b)+/lymphocyte antigen 6 complex
locus G (LY6G; GR1)+ myeloid cells
accumulate near the tumor [c]. The myeloid cells release
paracrine factors including S100 calcium binding protein A8
(S100A8; calgranulin A; MRP8) and S100A9 (calgranulin B;
MRP14) [d], which activate kinases such as MAP kinase 3 (MAPK3; ERK-1), MAPK1 (ERK-2), MAPK and ribosomal protein S6 kinase 70
kDa polypeptide 1 (RPS6KB1; S6K1) on the breast cancer
cells [e]. Activation of the
cancer-associated kinases promotes cancer cell survival and metastasis.
CXCR2 antagonists prevent CXCR2-expressing myeloid cells
from homing to cancer cells, blocking release of S100A8 and S100A9 and
subsequent kinase signaling that promotes cancer survival. Blocking CXCR2 could
reduce chemotherapy resistance and breast cancer metastasis.
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