Cancer-associated fibroblasts (CAFs) play a pivotal role in the development and progression of many human cancers. Recent studies have shown that Hedgehog (Hh) signalling modulates the stromal microenvironment and prepares a suitable niche for tumour metastasis. However, the detailed molecular mechanisms underlying CAF-mediated lymphangiogenesis have not been fully elucidated. Therefore, our goal is to illustrate whether Hh ligands can activate Hh signalling in CAFs in a paracrine fashion and elucidate the effect of CAFs on lymphangiogenesis. We determined here that Sonic Hedgehog (SHH) secreted by ovarian cancer (OC) cells activated Hh signalling in CAFs and promoted the proliferation of CAFs. Moreover, we co-injected SHH-overexpressing OC cells and CAFs in a xenograft model and found that the CAFs accelerated tumourigenesis and lymphangiogenesis in OC. Mechanistically, we found that SHH secreted by the OC cells induced VEGF-C expression in CAFs. Inhibition of Hh signalling in CAFs decreased VEGF-C expression and diminished the positive role of CAFs in supporting tumourigenesis and lymphangiogenesis in a murine xenograft model. Our results demonstrate that CAFs constitute a supportive niche for cancer lymphangiogenesis via the Hh/VEGF-C signalling axis and provide evidence for the clinical application of Hh inhibitors in the treatment of OC.
Metastasis is one of the most threatening aspects of cervical cancer. We developed a method to intraoperatively map the primary tumor, metastasis and metastatic sentinel lymph nodes (SLNs), providing real-time intraoperative guidance in cervical cancer.Methods: TMTP1, a tumor metastasis targeting peptide, was employed to modify the indocyanine green (ICG)-loaded poly (ethylene glycol)- poly (lactic-co-glycolic acid) (PEG-PLGA) micelles. The cervical cancer subcutaneous tumor model and lung metastasis model were established to determine the active targeting of ICG-loaded TMTP1-PEG-PLGA micelles (ITM) for the primary tumor and occult metastasis of cervical cancer. Human cervical cancer HeLa cells engineered by firefly luciferase were injected into the right hocks of BALB/c nude mice to develop the SLN metastasis model. The ITM and control ICG-loaded PEG-PLGA micelles (IM) were injected into the right hind footpads in the SLN metastasis model, and the migration and retention of micelles were recorded under near-infrared fluorescence. K14-HPV16 transgenic mice were also used to detect the image capability of ITM to target cancerous lesions.Results: ITM could actively target imaging of the primary tumor and cervical cancer metastasis. ITM quickly diffused from the injection site to SLNs along lymphatic capillaries and remained in the SLNs for 12 h. Moreover, ITM specifically accumulated in the tumor metastatic SLNs (T-SLNs), which could be successfully distinguished from normal SLNs (N-SLNs).Conclusion: ITM could achieve active targeting of the primary tumor, metastasis and T-SLNs, providing precise and real-time intraoperative guidance for cervical cancer.
The application of prostate-specific antigen (PSA) in the screening and diagnosis of prostate cancer (PCa) has improved the clinical management of PCa patients. However, the PSA assay has been faced with criticism due to its potential association with over-diagnosis and subsequent overtreatment of indolent patients. Matrix metalloproteinase-26 (MMP26) is a member of matrix metalloproteinases (MMPs) and has been reported to be highly expressed in many cancers. This investigation evaluated the potential of serum MMP26 as a biomarker for PCa. The level of serum MMP26 was measured by enzyme-linked immunosorbent assay (ELISA) in 160 subjects including PCa group (n=80), benign prostatic hyperplasia (BPH) group (n=40) and control group (n=40). Furthermore, we evaluated the expression of MMP26 in tissues by immunohistochemistry. The results showed the serum MMP26 levels were significantly higher in PCa group than in BPH group and control group. Similarly, the MMP26 protein was positive in PCa tissues and negative in BPH tissues and control tissues. In conclusion, these results suggested MMP26 could be used as a potential serum biomarker in the diagnosis of PCa.
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