The BCSC-enriched populations exhibited enhanced metastasis with higher STAT3 activation, while FLU administration inhibited tumor growth, angiogenesis and lung and liver metastasis, coinciding with decreased MMP-2 and MMP-9 levels in circulating blood.
Moreover, SERPINA3 siRNA could not only reduce live metastasis of mice, but also down-regulate the expression of Mmp-2 and Mmp-9 in liver metastasis tissues.
Moreover, these cells exhibited high metastasis in mice, and p-p65, MMP-2, and MMP-9 expression levels were elevated in the primary tumor and liver metastases.
The expression of six genes was significantly different in primary tumors compared with their matched liver metastases [CXCR4 (p < 0.001), THBS1 (p = 0.007), MMP 9 (p = 0.048), GST Pi (p = 0.050), TYMP (p = 0.042) and DPYD (p < 0.001)].
Our experimental results suggest that HCS has some anti-metastasis potential to suppress the growth of liver metastasis by decreasing the expression of MMP-2 and MMP-9 as well as VEGF.
Mice, intrasplenically transplanted with HCT116 cells and treated systemically with S100A4‑shRNA plasmids, showed a decrease of S100A4 and MMP9 expression levels, resulting in significantly reduced liver metastases (P = 0.005).
In contrast, MMP-2 and MMP-9 as well as TIMP-1, TIMP-2, and TIMP-3 expression in primary tumors of patients with liver metastases (M1) was significantly lower than in patients lacking liver metastases (M0).
These findings explain the efficacy of gelatinase-specific synthetic inhibitors on invasion and growth of tumor cells and attribute distinct functions of MMP-2 and MMP-9 to aspects of liver metastasis.
We conclude that MMP-9 is not up-regulated in tumor edge macrophages in liver metastases like in their primary tumor and local lymph node metastases, suggesting that disseminating colorectal cancer cells can adopt alternative proteolytic mechanisms for invasion depending on the local microenvironment.
High MMP-9 levels were also associated with visceral or bone metastasis (P = 0.027), elevated serum alkaline phosphatase level (P = 0.0009), and presence of liver metastases (P = 0.032).
The levels of TIMP-1, MMP-2 and MMP-9 mRNA were significantly higher in primary colorectal cancers than in their adjacent normal tissues, and those of the mRNAs for all four genes were significantly higher in liver metastases than in normal colorectal tissues.
Our data demonstrate a distinct pattern of MMP-9 and TIMP-1 mRNA expression in colorectal cancer and liver metastases suggesting distinct cellular origins as well as separate patterns of regulation.