Overcoming intrinsic and acquired drug resistance is a major challenge in treating cancer patients because chemoresistance causes recurrence, cancer dissemination and death. This review summarizes numerous molecular aspects of multi-resistance, including transporter pumps, oncogenes (EGFR, PI3K/Akt, Erk and NF-κB), tumor suppressor gene (p53), mitochondrial alteration, DNA repair, autophagy, epithelial-mesenchymal transition (EMT), cancer stemness, and exosome. The chemoresistance-related proteins are localized to extracellular ligand, membrane receptor, cytosolic signal messenger, and nuclear transcription factors for various events, including proliferation, apoptosis, EMT, autophagy and exosome. Their cross-talk frequently appears, such as the regulatory effects of EGFR-Akt-NF-κB signal pathway on the transcription of Bcl-2, Bcl-xL and survivin or EMT-related stemness. It is essential for the realization of the target, individualized and combine therapy to clarify these molecular mechanisms, explore the therapy target, screen chemosensitive population, and determine the efficacy of chemoreagents by cell culture and orthotopic model.

To investigate the role of PTEN and matrix metalloproteinase-7 (MMP-7) expression in tumorigenesis and progression of gastric carcinoma, their expression in 113 gastric carcinomas was studied by immunohistochemistry. Microvessel density (MVD) was counted using the anti-CD34 antibody. The expressions of PTEN and MMP-7, and MVD were compared with the clinicopathological parameters of tumors, and the relationship between PTEN and MMP-7 expression and MVD was analyzed. It was found that PTEN was expressed less frequently in primary gastric carcinoma cells than in adjacent epithelial cells (P < 0.05), whereas this was reversed for MMP-7 (P < 0.05). PTEN expression was negatively correlated with invasion, metastasis, growth pattern, Lauren's classification and histological classification (P < 0.05). Matrix metalloproteinase-7 expression was positively associated with tumor size, Borrmann's classification, invasive depth, metastasis and TNM staging (P < 0.05), but negative with PTEN expression (P < 0.05). A positive correlation of MVD with tumor size, invasive depth, metastasis and TNM staging was found (P < 0.05). Microvessel density depended on decreased PTEN expression and increased MMP-7 expression (P < 0.05). The results of the present study suggested that down-regulated PTEN expression and up-regulated MMP-7 expression were greatly implicated in tumorigenesis and progression of gastric carcinoma. Close correlation between PTEN on MMP-7 expression provided a novel insight into the regulatory effects of PTEN on MMP-7 expression in gastric carcinoma.

Aim: To investigate the pathobiological features of intestinal and diffuse-type gastric carcinomas in the Japanese population. Methods: The expression of fragile histine triad (FHIT), phosphatase and tensin homology deleted from human chromosome 10 (PTEN), caspase-3, Ki-67, mutant p53, matrix metalloproteinase (MMP)-2, MMP-9, and extracellular matrix metalloproteinase inducer (EMMPRIN) on tissue microarrays of gastric carcinomas by immunostaining was examined in comparison with the clinicopathological characteristics between intestinal and diffuse-type cases. Results: Intestinal-type carcinoma frequently occurred in old men, whereas the diffuse type comparatively occurred more in young women (p,0.05). The diffuse-type carcinoma was more inclined to invasion into muscularis propria, lymphatic invasion and lymph node metastasis, and belonged to higher International Union against Cancer (UICC) staging (p,0.05) compared with intestinal-type counterparts. Expression of FHIT, PTEN, Ki-67, caspase-3, mutant p53 and EMPPRIN was higher in intestinal-type carcinomas than in diffuse-type carcinomas (p,0.05). Kaplan-Meier analysis indicated that patients with intestinal-type carcinomas had a higher cumulative survival rate (p,0.05). Conclusion: Intestinal-type gastric carcinomas with a more favourable prognosis frequently show high levels of proliferation and apoptosis, and always accompany strong expression of FHIT, PTEN and mutant p53 and EMMPRIN. EMMPRIN expression might underlie the molecular basis of liver metastasis and higher proliferation of intestinal-type gastric carcinomas in Japan. Lauren's classification thus proved pathologically relevant for the clinical treatment of gastric carcinomas.

We previously observed that Pim-3 with serine/threonine kinase activity, was aberrantly expressed in malignant lesions of endodermderived organs, liver and pancreas. Because Pim-3 protein was not detected in normal colon mucosal tissues, we evaluated Pim-3 expression in malignant lesions of human colon, another endodermderived organ. Pim-3 was detected immunohistochemically in welldifferentiated (

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