Protein-bound polysaccharide K suppresses tumor fibrosis in gastric cancer by inhibiting the TGF-β signaling pathway

Abstract

Peritoneal carcinomatosis (PC) is the most frequent metastatic pattern of gastric cancer and its prognosis is extremely poor. PC is characterized by rich fibrosis and the development of obstructive disorders such as ileus, jaundice and hydronephrosis. Epithelial-mesenchymal transition (EMT) is one of the major causes of tissue fibrosis and transforming growth factor β (TGF-β) has a pivotal function in the progression of EMT. Protein-bound polysaccharide K (PSK) is a biological response modifier that can modulate the TGF-β/Smad signaling pathway in vitro. In the present study, we established a fibrotic tumor model using human peritoneal mesothelial cells (HPMCs) and a human gastric cancer cell line to evaluate whether PSK attenuates tumor fibrosis. HPMCs exposed to PSK did not undergo the morphological change from a cobblestone-like pattern to a spindle-shape pattern normally induced by treatment with TGF-β. Immunofluorescence further demonstrated that PSK suppressed TGF-β-induced overexpression of α-SMA in the HPMCs. We further showed that HPMCs contributed to the proliferation of tumor fibrosis by using a mouse xenograft model. Additionally, PSK treatment of these mice significantly reduced the area of observable tumor fibrosis. These results suggest that seeded cancer cells transformed HPMCs into myofibroblast-like cells through their release of TGF-β in the microenvironment, facilitating the development of fibrous tumors in organs covered with HPMCs. Therefore, our study indicates that PSK has potential utility as an anti-fibrotic agent in the treatment of gastric cancer patients with PC.

Establishing a xenograft mouse model of peritoneal dissemination of gastric cancer with organ invasion and fibrosis

“…Other studies suggest that the volume and composition of fibrous tissue in various organs are influenced by epithelial-mesenchymal transition (EMT), which differentiate into an extracellular matrix-producing myofibroblast characteristics [20–22]. We have previously reported that transforming growth factor-β1 (TGF-β1) mediated activation of HPMCs induces an EMT-like process, and that activated HPMCs function as a source of cancer-associated fibroblasts [16, 23]. Furthermore, we have established a subcutaneous tumor model using the gastric cancer cell line MKN45 in co-culture with HPMCs [16, 24].…”

Mechanisms of peritoneal dissemination in gastric cancer (Review)

“…PSK has been established to suppress the TGF signalling pathway (32). Shinbo et al (30) reported that PSK inhibits the EMT of HPMCs induced by TGF-β1 in vitro, and the co-inoculum of gastric cancer cells and HPMCs significantly inhibits fibrosis in xenograft tumours. These results suggest that PSK may be used to control tumour fibrosis in gastric cancer.…”

“…Several regulatory factors modulate the function of TGF-β1, including connective tissue growth factor (CTGF) (28), angiotensin II (Ang II) (29) and phytosulphokine (PSK) (30). CTGF is an important downstream effector of TGF-β1.…”

Anticancer Effects of Cyclocarya paliurus Polysaccharide (CPP) on Thyroid Carcinoma In Vitro and In Vivo

“…The total content of polysaccharide was determined to be 89.5%. Previous study showed that CPP exerts antiproliferation effect on various tumor cell lines [17][18][19]. We observed CPP inhibited cell proliferation and induced apoptosis in a pair of thyroid carcinoma cell lines including FRO, ARO, 8505C, SW579, K1, FTC133, and BCPAP.…”