Abstract
Efficient inhibition of tumor metastasis after resection of primary tumors is critical for cancer therapy. We have recently shown that Cyr61 promotes growth of pancreatic ductal adenocarcinoma (PDAC) through PI3k/Akt signaling-enhanced nuclear exclusion of p27. Here, we report that administration of adeno-associated viral vectors carrying a short-hairpin interfering RNA (shRNA) for Cyr61 via pancreatic duct significantly decreased the distal tumor metastases after resection of primary pancreatic tumor in mice. Moreover, Cyr61 depletion in PDAC cells significantly inhibited the tumor sphere formation in vitro, significantly decreased the growth of the subcutaneously transplanted tumor, and significantly decreased the incidence of tumor formation after serial adoptive transplantation into NOD/SCID mice. Finally, higher Cyr61 levels were detected in the PDAC specimens from the patients with distal tumor metastasis, compared to PDAC without metastasis at diagnosis. Together, our study suggests that suppression of Cyr61 in cancer stem cell-like cells in PDAC may inhibit tumor cell metastasis after resection of the primary tumor.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with an extreme low 5-year survival rate of the patients [1, 2]
Our study suggests that suppression of Cysteine-rich protein 61 (Cyr61) in cancer stem cell-like cells in PDAC may inhibit tumor cell metastasis after resection of the primary tumor
We found that Cyr61 depletion by short-hairpin interfering RNA (shRNA) significantly reduced both the mRNA (Figure 1E) and protein level (Figure 1F) in PANC-1 cells by more than 80%
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with an extreme low 5-year survival rate of the patients [1, 2]. A gene called K-ras has been shown as a genetic driver of pancreatic cancer initiation and progression [3]. The surgical removal of the primary tumor has been proposed to have both beneficial and adverse effects upon cancer spread and growth [6]. The removal of the primary tumor may result in growth of the metastatic cancer in the distal area [6]. Wound fluids contain a number of pro-angiogenic factors and those proangiogenic factors in wound fluids enter circulation and promote neo-angiogenesis in the distal area containing metastatic cancer cells [7,8,9,10]
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