This study reveals a novel mechanism by which EMMPRIN promotes tumor growth and metastasis by recruitment of BMDCs through controlling secretion and paracrine signaling of SDF-1 and VEGF.
CXCR7 is a receptor for chemokines including CXCL12 (stromal-derived factor-1), a molecule that promotes tumor growth and metastasis in breast cancer and other malignancies.
C-X-C motif chemokine 12/C-X-C chemokine receptor type 7 signaling regulates breast cancer growth and metastasis by modulating the tumor microenvironment.
Gene methylation associated with nodal metastasis included RARB (47·1 per cent for N- versus 31·7 per cent for N+; P = 0·008), chemokine ligand 12, CXCL12 (12·3 per cent for N- versus 8·9 per cent for N+; P = 0·021), and death-associated protein kinase 1, DAPK1 (19·3 per cent for N- versus 12·3 per cent for N+; P = 0·022).
There is also a significant correlation between the expression levels of CXCR4-CXCL12 axis and metastasis-related genes (E-cadherin and MMP2) in tumor samples with advanced stages of metastasis.
Signaling activated by binding of the C<i>X</i>C motif chemokine ligand 12 (CXCL12) to its cognate G protein-coupled receptor (GPCR), chemokine C<i>X</i>C motif receptor 4 (CXCR4), is linked to metastatic disease.
SIGNIFICANCE: An anti-semaphorin-4D vascular targeting agent demonstrates antitumor and prosurvival effects but also unravels a novel promalignant effect involving macrophage-derived SDF1 that promotes tumor invasion and metastasis, both in animal models and patients.<b>Graphical Abstract:</b> http://cancerres.aacrjournals.org/content/canres/79/20/5328/F1.large.jpg.<i>See related commentary by Tamagnone and Franzolin, p. 5146</i>.
The single-nucleotide polymorphism (SNP) rs1801157 (previously known as CXCL12-A/ stromal cell-derived factor-1 (SDF1)-3'A) in CXCL12/SDF1 gene was assessed in breast cancer, Hodgkin's lymphoma (HL), and non-Hodgkin's lymphoma (NHL), since the chemokine CXCL12, previously known as SDF1, and its receptor CXCR4 regulate leukocyte trafficking and many essential biological processes, including tumor growth, angiogenesis, and metastasis of different types of tumors.
The important role of CXCL12 in the invasion and metastasis of esophageal cancer stem cells was also confirmed by loss-of-function and gain-of-function strategies.
Results of in vitro cell studies showed that all prepared gels induced CEM tumor cell migration whereas only gels based on MC embedded with CXCL12 are able to capture them.
These data emphasize the importance of the CXCR4-SDF1 axis in EOC metastasis and suggest that this mechanism should be accounted for when targeting EOC metastasis.
Although this study will need further in vivo validation, our observations suggest that (a) silencing of CXCL12 in cervical cancer cells may be critical in migration and invasion, the key events in cancer cell metastases; (b) cervical cancer cells having down regulated CXCL12 are more prone to being attracted to CXCL12 expressed at secondary sites of metastases; and (c) CXCL12 inhibits anchorage independent cell growth via anoikis.
We previously demonstrated that the stromal cell-derived factor-1 (SDF-1; also known as CXCL12)/CXCR4 system is involved in the establishment of metastasis in oral squamous cell carcinoma.
C-X-C chemokine receptor type 4 and stromal cell-derived factor-1 were proven to play important roles in several types of cancer and in many biological processes connected with tumor growth, invasion, angiogenesis, and metastasis.
<i>in-silico</i> analysis finds that CXCL12-CXCR4 is associated with an increased expression of PDZK1, PI3k and Akt which lead the breast tumor towards metastasis.
Constitutive expression of CXCL12 in human colorectal carcinoma cells reduced orthotopic tumor formation and inhibited metastasis in severe combined immunodeficient mice.
Recent studies suggest that SDF-1 and CXCR4 are expressed in certain cancer cells, and malignant cells use this chemokine/receptor system to promote tumor progression and metastasis.
The expression of macrophage markers (CD163, CCL2/CCR2, CSF1/CSFR1, CXCR4/CXCL12), protumorigenic toll-like receptor pathway genes (CD14/TLR-1,-2,-4,-5,-6/MyD88), HLA-E, ecto-nuclease CD73/NT5E and inhibitory complement receptors (CD-59,-55,-46) remained high in metastases and represent potential therapeutic targets.