The Th1/Th2 ratio may be a good prognostic indicator and may also be a promising marker for estimating the effectiveness of surgery. NLR may also be a good prognostic indicator and may be a valid marker of tumor recurrence, and it appeared that some interaction between lymphocytes and neutrophils had occurred.
To determine whether lymphangiogenesis was associated with the development of colorectal carcinoma and whether the mean maximal diameter of lymphatic microvessels (LMMMD) or lymphatic microvessel density (LMVD) is associated with lymph node metastasis in early stage invasive colorectal carcinoma (T1 carcinoma), we used immunohistochemical staining with podoplanin to measure LMMMD and LMVD in intratumoral (LMMMDit, LMVDit) and peritumoral areas (LMMMDpt, LMVDpt) of T1 carcinomas (n=87). By comparing the LMMMD and LMVD in normal large intestine (n=10), adenoma (n=15), and Tis carcinoma (n=15), we found out that the LMVDpt in T1 carcinoma with lymphatic vessel invasion (LVI) was significantly high (P<0.001), and there was a significant decrease in LMMMDpt in T1 carcinoma (P=0.031). Both LMMMDpt and LMVDpt were significantly increased in the T1 carcinomas, with LVI compared with the T1 carcinomas without LVI (P=0.018, P=0.003). Multivariate analysis revealed that LVI and combined greater LMMMDpt and greater LMVDpt were associated with lymph node metastases (P=0.005, P=0.036). These results indicate that lymphangiogenesis might be induced in the surrounding tumor areas of the T1 colorectal carcinoma with LVI; thus, evaluation of the diameter and density of lymphatic microvessels is important in T1 colorectal carcinoma to predict lymph node metastases.
Abstract. The effects of Phx-3 on changes in intracellular pH (pH i ) in the MKN45 and MKN74 human gastric cancer cell lines were evaluated in order to determine the mechanism for the proapoptotic effects of 2-aminophenoxazine-3-one (Phx-3) on these cells. Phx-3 (100 μM) reduced pH i in MKN45 from 7.45 to 5.8, and in MKN74 from 7.5 to 6.2 within 1 min of engagement with these cells. Such a decrease of pH i was closely correlated with the dose of this phenoxazine and continued for 4 h. The activity of Na + /H + exchanger isoform l (NHE1), which is involved in H + extrusion from the cells, was dose-dependently suppressed by Phx-3 in these cells, and was greatly suppressed in the presence of 100 μM Phx-3. This result indicates that the decrease of pH i in MKN45 and MKN74 cells is closely associated with the inhibition of NHE1 in these cells. The morphology of these cells at 24 h after treatment with Phx-3 indicated shrinkage of the cells and condensation of the nuclear chromatin structure, which are characteristic of the apoptotic events in these gastric cancer cells. Cytotoxicity of Phx-3 against MKN45 and MKN74 cells was extensive because almost all MKN45 cells lost viability at 24 h in the presence of 20 μM Phx-3, and nearly 50% of the MKN74 cells lost viability in the presence of 50 μM Phx-3. These results suggest that rapid and extensive decrease of pH i in human gastric cancer MKN45 and MKN74 cells caused by Phx-3 might disturb intracellular homeostasis, leading to apoptotic and cytotoxic events in these cells. Phx-3 is a good candidate for therapeutics of gastric cancer that is intractable to conventional chemopreventive therapies.
IntroductionIt has been suggested that a decrease of intracellular pH (pH i ) precedes apoptotic events in cancer cells (1,2). Therefore, drugs to induce pH i reduction have been considered good candidates for treating cancer and causing programmed cell death (3). For example, cyclohexamide, etoposide, and camptothesin decrease pH i in cancer cells, leading to apoptosis of the cells (3-5); however, these drugs often exert significant adverse effects on the body (6,7).The oxidative phenoxazines [e.g., 2-amino-4,4·-dihydro-4·,7-dimethyl-3H-phenoxazine-3-one (Phx-1) and 2-aminophenoxazine-3-one (Phx-3)] exert anticancer effects on various species of cancer cells in vitro (8-10) and in vivo, without marked adverse effects (11-13). Recently, Che et al (14) reported that apoptotic events in KB-3-1 cells (human epidermoid carcinoma cell line) and K562 cells (human chronic myeloid leukemia cell line) are preceded by a decrease in pH i in cells treated with Phx-3, a phenoxazine produced by the reaction of o-aminophenol with bovine hemoglobin. However, the detailed mechanism for pH i decrease in these cancer cells with Phx-3 remains unclear.Regarding the regulation of pH i , it has been suggested that among Na + /H + exchangers, Na + /H + exchanger isoform 1 (NHE1) is ubiquitously present in the plasma membrane in the cells and plays a pivotal role in regulating pH i (15)(16)(17). Therefore...
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