No abstract

Labd-14-ene-8, 13-diol (sclareol) is a labdane-type diterpene, which has demonstrated significant cytotoxic activity against human leukemic cell lines, but its effect on solid tumor-derived cells is uknown. Here, we demonstrate that addition of sclareol to cultures of human colon cancer HCT116 cells results in inhibition of DNA synthesis, arrest of cells at the G(1) phase of the cell cycle, activation of caspases-8, -9, PARP degradation, and DNA fragmentation, events characteristic of induction of apoptosis. Intraperitoneal (ip) administration of sclareol alone, at the maximum tolerated dose, was unable to induce suppression of growth of HCT116 tumors established as xenografts in immunodeficient SCID mice. In contrast, ip administration of liposome-encapsulated sclareol, following a specific schedule, induced suppression of tumor growth by arresting tumor cell proliferation as assessed by detecting the presence of the cell proliferation-associated nuclear protein, Ki67, in thin tumor sections. These findings suggest that sclareol incorporated into liposomes may possess chemotherapeutic potential for the treatment of colorectal and other types of human cancer.

Abstract. The role of epidermal growth factor receptor (EGFR) in colorectal cancer (CRC) prognosis remains unclear despite the recent development of anti-EGFR treatments for metastatic disease. The heterogeneity of CRC may account for this discrepancy; proximal and distal CRC has been found to be genetically and clinicopathologically different. The aim of this study was to investigate the effect of tumor location on the association of EGFR with the conventional prognostic indicators (stage and grade) in CRC. Immunohistochemical assessment of EGFR was retrospectively performed in 119 primary CRC specimens and data were correlated with tumor stage and grade in the proximal and distal tumor subset. The molecular combination of EGFR with p53 (previously assessed in this sample) was similarly analyzed. EGFR positivity was detected in 34, 30 and 35% of the entire cohort, proximal and distal tumors, respectively. The pattern of EGFR clinicopathological correlation was found to differ by site. A reduction in the frequency of EGFR(+) with progression of stage and/or worsening of grade was observed proximally, whereas an opposite trend was recorded distally. Proximal tumors with stage I or with indolent features (stage I, welldifferentiated) exhibited a significantly higher proportion of EGFR positivity than other tumors of this location (p=0.023 and p=0.022, respectively) or corresponding distal tumors (p=0.018 and p=0.035, respectively). Moreover, the co-existence of EGFR and high p53 staining (accounting for 11% of cases) was found in a significantly higher proportion of stage IV tumors compared to other stages (p=0.004), although only for the distal subset. Proximal and distal tumors showed various patterns of EGFR variation with disease progression and aggressiveness. This disparity provides further support to the hypothesis that these particular subsets of CRC are distinct tumor entities. It may also be suggestive of a potentially different therapeutic approach according to tumor site, particularly regarding anti-EGFR targeted treatment. IntroductionColorectal cancer (CRC) is one of the most common malignancies and remains a major cause of cancer mortality in the West (1). It is also a multi-pathway disease with disparate subgroups exhibiting distinct genetic and clinicopathological features, and probably different outcomes (2). This may be the main reason for the variability in treatment response observed among patients of the same disease stage. Therefore, a combination of the conventional TNM staging classification (at present, the major prognostic indicator) with certain molecular markers involved in CRC tumorigenesis, with verified prognostic and predictive impact, is one of the main objectives of research worldwide (3).Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein member of the tyrosine-kinase receptor family, encoded by the c-erB1 proto-oncogene and is considered as a major regulator of several distinct cellular pathways. Activation of EGFR promotes carcinogenesis, by increasing prol...

Abstract. Colorectal cancer (CRC) is considered to develop through the conventional adenoma-carcinoma sequence. However, the existence of de novo carcinogenesis, without any intervening precursor lesions, has been suggested for certain morphologically different tumors lacking polypoid characteristics. The presence of such tumors, along with their correlation with cardinal clinicopathological parameters, such as stage, grade and site, was retrospectively investigated in a series of 119 surgically treated CRC cases. The absence of particular polypoid characteristics (adenomatous remnants or coexisting polyps in the tumor vicinity) in combination with an infiltrative (or ulceroinfiltrative) growth pattern, were the criteria defining the nonpolypoid origin. The recorded frequencies of remnants, coexisting polyps and infiltrative tumors were 7, 5, 9 and 32%, respectively. The incidence of cases meeting the above-mentioned criteria was 28.5%. These nonpolypoid lesions exhibited a predilection for proximal anatomical site (P=0.04), probably associated with their infiltrative pattern. Most importantly, de novo lesions (unlike polypoid) were rarely found among cases with indolent tumor characteristics (stage I or grade I, P=0.008), showing a considerably different overall pattern of distribution by stage and grade as compared to that of polypoid tumors (P=0.03). The fact that nonpolypoid CRCs appeared to be clinicopathologically different from their polypoid counterparts is supportive of possible de novo origin and suggestive of a likely worse clinical behavior. The impact of these findings should be investigated to determine potential applications in the diagnosis, treatment and surveillance of these lesions.

Abstract. p53 and Bcl-2 (both regulators of cell apoptosis) have been considered to be involved in the initiation and progression of the colorectal tumorigenic process, respectively. In this study, we investigated their association with tumor stage and grade -both substantially affecting prognosis. Immunohistochemical assessment of p53 and Bcl-2 was retrospectively conducted (using DO-7 and Ca-124 monoclonal antibodies, respectively) in 119 surgically resected colorectal carcinomas, and the results were correlated to tumor stage and grade. The proportion of tumors positively stained was 70% for p53 and 46% for Bcl-2, whereas co-expression of both markers was observed in 28% of cases. Tumors exhibiting the highest p53 staining (>60% stained cells) were more frequently found in disease stage IV (p=0.03), while Bcl-2 positivity showed a predilection for earlier stage (p=0.02) and better grade (p=0.028). The associations of both markers with stage, along with a reciprocal relationship between p53(+) and Bcl-2(+) tumors (p=0.02), stronger for cases with p53 staining >30% (p=0.007), remained significant only for distal tumors. The distinct correlations of p53 and Bcl-2 with disease progression and aggressiveness (being influenced by the extent of staining and tumor site) may be clinically useful in the determination of high-risk colorectal cancer cases.