<Originals>Involvement of cellular fibrinolysis and apoptosis of human pancreatic carcinoma cells in their metastasis

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The plasminogen activation (PA) system of several cancer tissues has been shown to play an important role in invasion and metastasis. The apoptotic induction of cancer cells has also been studied intensively in the fields of chemotherapy or radiation therapy. However, the detailed mechanisms of their involvement in cancer metastasis are still unknown. To elucidate the role of the PA system and apoptotic induction in liver metastasis of pancreatic cancer, immunohistochemical studies were performed from the standpoints of fibrinolytic factors (urokinase type PA (uPA), uPA receptor (uPAR), plasminogen activator inhibitor-1 (PAI-1), and PAI-2), cell proliferating index, apoptotic index, Bax protein expression and related substances, such as human hepatic growth factor (HGF) and c-met protein expression. The expression of each immunoreactivity in nine surgical materials without liver metastasis at the operation showed the similar trends to the overall positive rate of the autopsied samples, revealing that the autopsied samples could be used in the studies of cellular fibrinolysis and apoptosis in relation to the metastasis. Using 26 autopsied samples, immunoreactivity of each factor was compared between liver metastasis (H group) and peritoneal dissemination (P group). The overall positive rates of uPA, uPAR, PAI-1 and PAI-2 for immunohistochemical staining in cancer and stromal tissues were 96.1%, 57.7%, 84.6% and 57.7%, respectively. Compared with P group, however, H group showed significantly higher positive ratios of uPAR and PAI-2,90.9% and 90.9%, respectively. These findings suggest that increased expression of uPAR in combination with uPA expression induced enhancement of tumor cell detachment and degeneration of extracellular matrix and intravascular tumor cell invasion. A significantly higher ratio of PAI-2 expression in the H group implies that PAI-2 has an important role in hematogenous liver metastasis through inhibition of cancer cell proteolysis. The positive HGF and c-met immunoreactivity were 81.1% and 72.7% in the H group and 40.0% and 15.4% in the P group, respectively showing significantly higher ratio in H group. Significantly high expression of HGF and c-met gene in the H group implies that HGF produced by stromal cells initially and cancer cells finaly as autocrine response promotes the uPA and uPAR production and secretion in cancer cells, yielding the accelerated cancer cells invasion through plasminogen activation. Apoptotic indices in the H group and P group were 17.4±32.0 and 148.6±192.6 respectively showing a significantly lower index in the H group. Bax protein immunoreactivity in the H group and P group was 18.1% and 86.7% respectively, showing a significantly lower ratio in the H group. Significantly lower ratios of apoptosis and Bax protein induction are agreeable with the significantly high expressions of HGF and c-met gene in the H group, supporting that enhanced HGF production in cancer tissue inhibits the apoptosis of pancreatic cancer cells in the H group. Thus, it might be concluded that the combination of the accelerated cancer cell invasion through plasminogen activation and the depressed apoptosis of cancer cells through enhanced HGF expression play the key roles in hematogenous liver metastasis in pancreatic cancer.

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