Laminin ß3 expression as a prognostic factor and a predictive marker of chemoresistance in colorectal cancer.

OBJECTIVE: Laminin-332, a marker of epithelial-mesenchymal transition, is composed of a heterotrimer of α3, ß3 and γ2 chains that regulates cell adhesion and migration. This study aimed to disclose the respective clinical significance of laminin ß3 immunoexpression in colorectal cancer as a prognostic factor and a predictive marker of chemoresistance. METHODS: Tissue specimens from 323 Stage II and 232 Stage III colorectal cancer patients who underwent curative resection were assessed using laminin ß3 immunostaining. RESULTS: Among Stage III colorectal cancer patients, comparisons of 5-year disease-free survival rates revealed a poorer prognosis for the laminin ß3-high group than for the laminin ß3-low group (52.3 vs. 70.7%, P = 0.038), while there was no significant difference among Stage II patients. Among laminin ß3-low Stage III patients, those who received adjuvant chemotherapy showed marginally better disease-free survival than those who did not receive it (75.8 vs. 62.8%; P = 0.096). Furthermore, multivariate analysis corroborated a distinct benefit of adjuvant chemotherapy in laminin ß3-low patients (P = 0.035; hazard risk ratio = 1.66). Analyses of the laminin ß3-high group, however, failed to show significance. CONCLUSIONS: Laminin ß3 chain immunoreactivity was a poor prognostic factor for Stage III colorectal cancer patients, and laminin ß3-high patients of Stage III colorectal cancer derived no survival benefit from adjuvant chemotherapy.

Differential clinical benefits of 5-fluorouracil-based adjuvant chemotherapy for patients with stage III colorectal cancer according to CD133 expression status.

OBJECTIVE: CD133 has been recently identified as a marker of putative cancer stem cells in colorectal tumors. The ability of cancer stem cells to resist chemotherapy was clinically highlighted; however, whether CD133 expression can predict chemoresistance remains controversial. The objective of the study was to determine the relationship between clinical benefits of adjuvant chemotherapy and CD133 expression status in colorectal cancer. METHODS: We enrolled 234 patients with Stage III colorectal cancer who underwent curative resection. Among them, 149 received 5-fluorouracil-based adjuvant chemotherapy (chemotherapy group) and 85 did not (surgery-alone group). We immunohistochemically stained the specimens for CD133 on specimens evaluated the benefits of adjuvant chemotherapy according to CD133 expression using the Kaplan-Meier method and log-rank test. RESULTS: A comparison of disease-free survival between both the groups revealed a significant 3-year disease-free survival benefit of adjuvant chemotherapy in CD133-negative (92.2% versus 74.5%; P = 0.004), but not in CD133-positive patients (46.8% versus 52.9%; P = 0.67). Multivariate analysis corroborated the benefits of adjuvant chemotherapy in CD133-negative (P = 0.003, hazard ratio = 0.26), but not in CD133-positive patients. CONCLUSIONS: CD133-positive patients showed resistance to 5-FU-based chemotherapy, while CD133-negative patients experienced significant survival benefits from adjuvant chemotherapy not shared by CD133-positive patients.

Enteral refeeding rapidly restores PN-induced reduction of hepatic mononuclear cell number through recovery of small intestine and portal vein blood flows.

BACKGROUND: Absence of enteral nutrition (EN) reduces hepatic mononuclear cell (MNC) numbers and impairs their functions. However, enteral refeeding (ER) for as little as 12 hours following parenteral nutrition (PN) rapidly restores hepatic MNC numbers. We hypothesized that changes in small intestine and portal vein blood flows related to feeding route might be responsible for this phenomenon. METHODS: In experiment 1, mice (n = 19) were randomized to Chow (n = 5), PN (n = 7) or ER (n = 7) groups. The Chow group was given chow ad libitum with intravenous (IV) saline for 5 days. The PN group was fed parenterally for 5 days, while the ER group was re-fed with chow for 12 hours following 5 days of PN. Then, small intestine and portal vein blood flows were monitored and hepatic MNCs were isolated and counted. In experiment 2, the effects of intravenous administration of prostaglandin E(1) (PGE(1)) on hepatic MNC numbers were examined in fasted mice for 12 hours. Mice (n = 28) were randomized to Control (n = 8), PG0 (n = 10), or PG1 (n = 10) groups. The Control group was fed chow ad libitum with IV saline, while the PG0 and PG1 groups were fasted for 12 hours with infusions, respectively, of saline and PGE(1) at 1 microg/kg/minute. Blood flows and hepatic MNC numbers were examined. RESULTS: Experiment 1: ER restored PN-induced reductions in small intestine and portal vein blood flows and hepatic MNC number to the levels in the Chow group. Small intestine and portal vein blood flows correlated positively with hepatic MNC number. Experiment 2: Fasting decreased small intestine and portal vein blood flows and hepatic MNC number. However, PGE(1) restored portal vein blood flow to the level of the Control group, and moderately increased hepatic MNC number. There was a positive correlation between portal blood flow and hepatic MNC number. CONCLUSIONS: Reduced small intestine and portal vein blood flows may contribute to impaired hepatic immunity in the absence of EN. ER quickly restores hepatic MNC number through recovery of blood flow in both the small intestine and the portal vein.

Enteral nutrition rapidly reverses total parenteral nutrition-induced impairment of hepatic immunity in a murine model.

BACKGROUND & AIMS: Total parenteral nutrition (TPN) impairs host immunocompetence, a mechanism possibly underlying the high morbidity of infectious complications in critically ill patients. Our recent study demonstrated TPN to reduce the number and function of hepatic mononuclear cells (MNCs) and to worsen survival after intraportal Pseudomonas challenge in mice. The present study examined the duration of enteral nutrition (EN) needed to reverse TPN-induced changes in hepatic MNCs in a murine model. METHODS: Male ICR mice (6 weeks) received 5 days of TPN followed by 0 (TPN), 12 (EN12), 24 (EN24), 48 (EN48) or 72 (EN72)h of chow feeding. Control mice (Control) were given chow with intravenous saline infusions for 5 days. After nutritional support, hepatic MNCs were isolated and counted. Lipopolysaccharide (LPS) receptor expressions (CD14 and TLR4/MD2) on Kupffer cells were analyzed by flowcytometry. In addition, TPN, EN12, EN48 and control mice were given intraportal Pseudomonas challenge and survival was monitored. RESULTS: The TPN group was significantly lower in hepatic MNC number and LPS receptor expressions than the Control group. However, EN quickly reversed TPN-induced hepatic impairments in MNC loss within 12h, CD14 expression within 48 h and TLR4/MD2 expression within 24h. Survival of the EN48 group was significantly improved as compared with the TPN and EN12 groups. CONCLUSIONS: EN rapidly reverses TPN-induced impairment of hepatic immunity along with increased hepatic MNC numbers and LPS receptor expressions on Kupffer cells.