Prokineticin-1 induces normal lymphangiogenic activity and is involved in lymphangiogenesis and lymph node metastasis in colorectal cancer.

BACKGROUND: Prokineticin family correlates with important roles in several biological processes, including homeostasis. We discovered novel functions of prokineticin1 (PROK1) in lymphangiogenesis and lymphnode metastasis in colorectal cancer. MATERIALS AND METHODS: We examined changes in the number of lymphatic endothelial cells after PROK1 stimulation. PROK1 protein was stimulated with subcutaneously implanted in mice. Also a high-PROK1-expressing colorectal cancer cell line and anti-PROK1 antibody(Ab) were subcutaneously implanted in mice, and then examine lymphangiogenesis. PROK1 expression and the number of lymph vessels were examined in the primary lesion of 391 patients whose colorectal tumors had been resected. RESULTS: When PROK1 was used as a stimulus, the number of lymphatic cells increased compared to unstimulated cells. And the number of lymph vessels in the skin of mice increased compared to mice implanted without PROK1. The number of lymph vessels in the primary tumor tissue increased when PROK1 was highly expressed compared to cases with non-detectable PROK1 expression. When PROK1 was expressed in human colorectal tumors, the rate of lymphnode metastasis was significantly higher than that in cases with non-detectable PROK1 expression. CONCLUSIONS: PROK1 is a lymphangiogenic factor involved in the formation of new lymph vessels and lymphnode metastasis in human colorectal cancer.

[A Long Term Survival Case of Gastric Cancer with Peritoneal Dissemination Responding to Intraperitoneal Chemotherapy].

A 32-year-old woman was admitted our hospital due to epigastric discomfort. The patient diagnosed as having scirrhous carcinoma of the stomach by upper gastrointestinal scope. Peritoneal dissemination and ovarian metastasis were confirmed by the diagnostic laparoscopy. Therefore, combination chemotherapy with S-1 and intraperitoneal chemotherapy(ip)with docetaxel (DTX) was started. After 2 courses chemotherapy, laparoscopy was performed again. Peritoneal dissemination was scarred, but biopsy showed altered AE1/AE3 positive cells, and increased left ovarian metastasis, so systemic chemotherapy was changed to DCS chemotherapy and added DTX ip. After 4 courses chemotherapy and 7 months after the first diagnosis, subtotal gastrectomy, hysterectomy and bilateral adnexectomy were performed because the cytology and tumor marker remained within normal range. In histopathological diagnosis, the effect of chemotherapy was Grade 2 at the primary site and Grade 3 at the metastatic site. Nine years have passed since the initial diagnosis and she has no relapse with postoperative adjuvant chemotherapy.

[Examination of Prognosis and Adjuvant Chemotherapy in Stage â ¡ and Stage â ¢ Resected Colorectal Cancer in the 9th Edition Japanese Classification of Colorectal Carcinoma].

In the 9th edition Japanese Classification of Colorectal Carcinoma, Stage Ⅱ and Stage Ⅲ colorectal cancer(CRC)were subdivided by TNM classification on invasion and number of lymph node metastases. We studied prognostic comparison and relation of adjuvant chemotherapy at the new classification. We included 400 cases with resected Ⅱ and Ⅲ CRC from 2007 to 2014. Ⅱa/Ⅱb/Ⅱc/Ⅲa/Ⅲb/Ⅲc were 97/68/20/24/124/67 cases. Adjuvant chemotherapy was performed at 19/32/45/66/59/70% in Ⅱa/Ⅱb/Ⅱc/Ⅲa/Ⅲb/Ⅲc, with or without adjuvant chemotherapy at each stage survival rates were compared. In Ⅱa/Ⅱb/Ⅱc, DSS was 97/97/82% and DFS was 89/88/76%, and the prognosis of Ⅱc was significantly worse. In Ⅲa/Ⅲb/Ⅲc, DSS was 95/86/57% and DFS was 82/77/41%. By the presence or absence of adjuvant chemotherapy, significantly differences were obtained at Ⅲb and Ⅲc. Prognosis of Ⅱc was almost same as Ⅲb, and prognosis of Ⅲa was almost same as Ⅱb. Therefore, we considered adjuvant chemotherapy with oxaliplatin should be performed to Ⅱc, Ⅲb, and Ⅲc.

Hepatic artery infusion therapy is effective for chemotherapy-resistant liver metastatic colorectal cancer.

BACKGROUND: Systemic FOLFOX (folinic acid (leucovorin (LV)), 5-fluorouracil (5-FU), and oxaliplatin), FOLFIRI (LV, 5-FU, and irinotecan), or FOLFOXIRI (5-FU, leucovorin, oxaliplatin, and irinotecan) chemotherapy regimens and additional molecular-target treatments, including anti-vascular endothelial growth factor, anti-epidermal growth factor receptor, and anti-multi-kinase antibodies, have been recommended for unresectable recurrent colorectal cancers. However, no effective treatments are currently available for cases refractory to these therapies. Therefore, the development of alternative therapies is desired. In the present study, we administered and observed the effectiveness of hepatic artery infusion therapy (HAIC) in patients with unresectable liver metastatic colorectal cancers refractory to systemic chemotherapy. In addition, we observed that in an experimental system with anticancer drug-resistant colorectal cancer lines, apoptosis and cell death could be induced by increasing anticancer drug concentrations. METHODS: The subjects had liver metastatic colorectal cancers that were unresponsive to systemic chemotherapy (FOLFOX/FOLFIRI) or to additional molecular-target therapies for progressive disease. Hepatic infusion tube placement was conducted according to the Seldinger method to insert a catheter with a side hole via the right femoral artery. A coiling procedure was performed to prevent drug influx into the gastroduodenal artery. Ten subjects were selected, and the results were evaluated after HAIC (5-FU and LV administered once weekly). Moreover, anticancer drug-resistant colorectal cancer lines were subsequently prepared to investigate whether increased anticancer drug concentrations could induce apoptosis or cell death. RESULTS: Of the 10 subjects, 3 (30 %) showed partial response and 4 (40 %) showed no change according to computed tomography imaging findings obtained after hepatic artery infusion. The disease control rate was 70 %. Eight subjects had improved quality of life. Survival time ranged from 2 to 16 months (median, 9 months). Meanwhile, we found that higher anticancer drug concentrations induced apoptosis and cell death in an anticancer drug-resistant colorectal cancer cell line. CONCLUSIONS: HAIC was effective in some systemic chemotherapy-resistant colorectal cancers with liver metastases and should be considered as an effective palliative therapy. This supports the finding that apoptosis and cell death could be induced in anticancer drug-resistant colorectal cancer cells in a drug concentration-dependent manner.

Expression of prokineticin-receptor2(PK-R2) is a new prognostic factor in human colorectal cancer.

The increased invasiveness of colorectal cancer cells is important for progression and metastasis to the surrounding organs. According to recent molecular biological studies, signaling through transmembrane Prokineticin-Receptor2(PK-R2) is likely involved in the ability of tumor cell to invade. However, no studies have evaluated the relationship between PK-R2 expression, ability of cancer to invade/metastasize, and patient prognosis in cases of resected colorectal cancer. Accordingly, we have examined these factors in the present study.Immunohistochemical staining was performed to detect PK-R2 in the primary lesion and adjacent normal large intestine mucosa of 324 colorectal cancer patients who underwent resection surgery at our department. Additionally, we conducted clinicopathologic examinations and analyzed patient prognoses with the Kaplan-Meier method. Further, multivariate analysis was conducted using a cox-proportional hazard model.PK-R2 expression was observed on the cellular membrane of the primary lesion in 147 of 324 cases (45.3%) of human colorectal cancer. PK-R2 expression was associated with a higher incidence of vascular invasion, lymph node metastasis, hepatic metastasis, and hematogenous metastasis. Further, prevalence of PK-R2 expression increased as tumor stage increased. In stage III curative resection cases, where recurrence is the most serious problem, cases that expressed PK-R2 had a significantly lower 5-year survival rate (82.1% versus 66.8%) and higher recurrence compared to those cases with no PK-R2 expression. In the multivariate analysis for prognosis, PK-R2 expression was found to be an independent factor(ratio2.621).PK-R2 expression could be one of the new prognostic factors in human colorectal cancer.

Prokineticin 2 (PROK2) is an important factor for angiogenesis in colorectal cancer.

The Prokineticin 2 (PROK2) is correlated with indispensable in maintaining the homeostasis of healthy human tissues. Herein, we examined the role of PROK2 in human colorectal cancer.After total RNA extraction from 6 colorectal cancer cell lines, we examined the expression of PROK2 mRNA. For investigating angiogenesis and tumor growth in mice, the PROK2 gene was transfected into colorectal cancer cell lines having low PROK2 mRNA expression. In addition, small interfering RNA (siRNA) was transfected into colorectal cancer cell lines having high PROK2 mRNA expression for investigation of angiogenesis and tumor growth in mice.From 6 colorectal cancer cell lines studied, PROK2 mRNA expression was increased in 3 cell lines. When the PROK2 gene was transfected into the colorectal cancer cell line with low PROK2 mRNA expression, angiogenesis and tumor growth in mice increased significantly compared to the cell line with the control vector.When PROK2 siRNA was transfected into colorectal cancer cell lines with high PROK2 mRNA expression, angiogenesis and tumor growth in mice were suppressed significantly compared to the cell line with siRNA (control).This is the first report of the association of PROK2 as an angiogenic growth factor in colorectal cancer.

Cancer stem cell marker in circulating tumor cells: expression of CD44 variant exon 9 is strongly correlated to treatment refractoriness, recurrence and prognosis of human colorectal cancer.

BACKGROUND/AIM: The expression of the CD44 variant exon 9 (CD44v9) was investigated in order to elucidate its significance for cancer stem cells in circulating human colorectal cancer cells (CTCs). MATERIALS AND METHODS: After peripheral blood was drawn from patients with colorectal cancer, CTCs were collected. Using the reverse transcription-polymerase chain reaction method, we examined the relationship between expression of CD44v9 mRNA and prognosis. RESULTS: In 60 out of 150 patients with colorectal cancer, expression of CD44v9 mRNA was positive in CTCs. In patients with stage III disease, the 5-year survival rate was 89% for patients with negative CD44v9 expression, whereas it was 52.4% in patients with positive expression (p<0.05). In patients with stage IV unresectable cancer, the 2-year survival rate was 70.1% in cases with CD44v9-negative expression and 33.3% in cases of positive expression (p<0.05). CONCLUSION: CD44v9 mRNA in the CTCs of colorectal cancer is useful as a factor predicting recurrence, prognosis, and treatment efficacy.

Protein-bound polysaccharide K reduced the invasive ability of colon cancer cell lines.

BACKGROUND/AIM: A protein-bound polysaccharide, polysaccharide K (PSK), is a non-specific immunological agent used in the treatment of colon cancer, however few studies have investigated the genetic changes in cancer cells treated with PSK. Therefore, we investigated the effect of PSK on cancer cell invasion, which is an indicator for the malignancy of colon cancer cell lines, and performed additional genetic analyses. MATERIALS AND METHODS: We performed Matrigel invasion assay to examine whether the invasive ability of colon cancer cell lines HT29, HCT116, and LoVo would be impacted upon stimulation with PSK. We used reverse transcription-polymerase chain reaction (RT-PCR) to evaluate for changes in the expression of matrix metalloproteinases (MMP)-2 and - 9 upon stimulation of colon cancer cell lines with PSK. RESULTS: The mean number of invasive cells in untreated HCT116, HT29, and LoVo cells was 146, 81, and 65, respectively, while that in PSK-treated cell lines was reduced to 24, 7, and 4, respectively. mRNA levels of MMP2 and MMP9 in PSK-stimulated cell lines were significantly lower than those in unstimulated cell lines. CONCLUSION: PSK reduced the expression of MMP2 and MMP9 mRNAs and cell invasion of this panel of colon cancer cell lines.

Effect of epoxides and α-methylene-γ-lactone skeleton of sesquiterpenes from yacon (Smallanthus sonchifolius) leaves on caspase-dependent apoptosis and NF-κB inhibition in human cercival cancer cells.

The present study investigated the cytotoxicity of enhydrin (1), uvedalin (2) and sonchifolin (3) in cervical cancer cells. We have found that SLs 1-3 in doses in range of 0.22-10 µM inhibited cell proliferation and induced apoptosis in both a dose- and time-dependent fashion. A significant cell death induction was supported by morphological studies. The apoptotic effect is associated with caspase-3/7 activation and NF-кB inhibition. Interestingly, enhydrin possessing two epoxide units was found to be the most cytotoxic compound. Therefore it can be assumed that number of epoxides and existence of α-methylene-γ-lactone moiety are essential for the acceleration of apoptosis.