AKT-mediated enhanced aerobic glycolysis causes acquired radioresistance by human tumor cells

Background and purpose

Cellular radioresistance is a major impediment to effective radiotherapy. Here, we demonstrated that long-term exposure to fractionated radiation conferred acquired radioresistance to tumor cells due to AKT-mediated enhanced aerobic glycolysis.

Material and methods

Two human tumor cell lines with acquired radioresistance were established by long-term exposure to fractionated radiation with 0.5 Gy of X-rays. Glucose uptake was inhibited using 2-deoxy-d-glucose, a non-metabolizable glucose analog. Aerobic glycolysis was assessed by measuring lactate concentrations. Cells were then used for assays of ROS generation, survival, and cell death as assessed by annexin V staining.

Results

Enhanced aerobic glycolysis was shown by increased glucose transporter Glut1 expression and a high lactate production rate in acquired radioresistant cells compared with parental cells. Inhibiting the AKT pathway using the AKT inhibitor API-2 abrogated these phenomena. Moreover, we found that inhibiting glycolysis with 2-deoxy-d-glucose suppressed acquired tumor cell radioresistance.

Conclusions

Long-term fractionated radiation confers acquired radioresistance to tumor cells by AKT-mediated alterations in their glucose metabolic pathway. Thus, tumor cell metabolic pathway is an attractive target to eliminate radioresistant cells and improve radiotherapy efficacy.     

Long-term results of breast volume replacement using an inframammary adipofascial flap after breast-conserving surgery

We have used an inframammary adipofascial flap for breast-conserving reconstruction in the inferior portion of the breast since 2005. The aim herein is to report this oncoplastic procedure in detail, including the long-term results. The surgical procedure was as follows: A skin incision is made at the inframammary line. After partial resection of the breast, a tongue-shaped flap of the fat and the anterior sheath of the rectus abdominis muscle are pulled up in the inframammary area. The flap is then inserted into the breast area where the tumor was removed, and it is secured with absorbable sutures to the surrounding breast tissue. When making the flap, it is very important to preserve several intercostal perforators around the inframammary line. Cosmetic results at more than 5 years after the operation in the 5 patients were assessed using photographs. The results were found to be good in 4 cases (80%) and poor in 1 case. The poor outcome was a case with 100% fat necrosis of the flap. This surgical procedure is easy to perform, and the long-term cosmetic outcomes were good, without complications. We consider this procedure to be useful for breast-conserving reconstruction after breast cancer occurring in the inferior portion of the breast.     

Is evaluation of the presence of prepectoral edema on T2-weighted with fat-suppression 3 T breast MRI a simple and readily available noninvasive technique for estimation of prognosis in patients with breast cancer?

Background

The specificity of breast MRI is only moderate. The unsatisfactory specificity of breast MRI has prompted evaluation of high signal intensity (SI) on T2-weighted imaging (T2WI). The purpose of the study was to investigate the prevalence of prepectoral edema determined using high SI on T2WI with fat-suppression 3 T MRI and to correlate its presence with prognostic factors of breast cancer.

Methods

The retrospective study comprised 589 consecutive histopathologically confirmed lesions, 460 malignant and 129 benign, identified by 3 T MRI. Presence of prepectoral edema was evaluated on T2WI with fat suppression, and its diagnostic value for malignancies and correlation with clinicopathological findings in histopathologically confirmed breast cancer were assessed.

Results

Prepectoral edema was present in 54 of the 460 breast cancers (9 % of the total 589) and none of the 129 benign lesions. Its sensitivity and specificity were 12 and 100 %, respectively. The positive predictive value was 100 %. Young age (p = 0.01), large tumor size (p < 0.0001), high histological grade (p < 0.0001), invasive ductal carcinoma (p < 0.0001), high lymphovascular invasion degree (p < 0.0001), high axillary lymph node positivity (p < 0.0001), high inflammatory breast cancer rate (p < 0.0001), high neoadjuvant chemotherapy rate (p < 0.0001), and chemoresistant breast cancers (p < 0.0001) were significantly associated with prepectoral edema. There was no association of the morphological lesion type on MRI and dynamic enhancement imaging pattern with the presence of prepectoral edema.

Conclusion

Prepectoral edema has low prevalence but is specific for breast cancer and correlated with prognostic factors.     

Galectin-9 as a prognostic factor with antimetastatic potential in breast cancer.

PURPOSE: Galectin-9, a member of the beta-galactoside-binding galectin family, induces aggregation of certain cell types. We assessed the contribution of galectin-9 to the aggregation of breast cancer cells as well as the relation between galectin-9 expression in tumor tissue and distant metastasis in patients with breast cancer. EXPERIMENTAL DESIGN: Subclones of MCF-7 breast cancer cells with high or low levels of galectin-9 expression were established and either cultured on plastic dishes or transplanted into nude mice. The tumors of 84 patients with breast cancer were tested for galectin-9 expression by immunohistochemistry. The patients were followed up for 14 years. RESULTS: MCF-7 subclones with a high level of galectin-9 expression formed tight clusters during proliferation in vitro, whereas a subclone (K10) with the lowest level of galectin-9 expression did not. However, K10 cells stably transfected with a galectin-9 expression vector aggregated in culture and in nude mice. Ectopic expression of galectin-9 also reduced MCF-7 cell adhesion to extracellular matrix proteins. Tumors of 42 of the 84 patients were galectin-9 positive, and those of 19 of the 21 patients with distant metastasis were galectin-9 negative. None of the 13 patients with galectin-9-positive tumors and lymph node metastasis up to level II manifested distant metastasis. The cumulative disease-free survival ratio for galectin-9-positive patients was more favorable than that for the galectin-9-negative group (P < 0.0001). Multivariate analysis revealed that galectin-9 status influenced distant metastasis independently of and to a greater extent than lymph node metastasis. CONCLUSIONS: Galectin-9 is a possible prognostic factor with antimetastatic potential in breast cancer.     

Blockade of paracrine supply of insulin-like growth factors using neutralizing antibodies suppresses the liver metastasis of human colorectal cancers.

Environmental stimuli, such as organ-specific growth factors, can influence the metastatic potential of a tumor. The liver is the main source of insulin-like growth factors (IGFs). The importance of IGF signal in hepatic metastasis has been clarified mainly by IGF-I receptor targeting strategies. This study aims to confirm these precedent reports by novel tool, neutralizing antibodies against IGFs and to show that IGFs are promising therapeutic targets for hepatic metastasis in vivo. Hepatic metastasis was induced by intrasplenic injection of human colorectal cancer cell line, HT29. The antimetastatic effects of three antibodies (anti-mouse IGF-I, anti-mouse IGF-II, and anti-human/mouse IGF-II designated KM1468) were tested singly or in combination in the early phase of metastasis. The dose escalation effect of KM1468 and its survival benefit were examined in the early and late phases of metastasis. The mechanism of IGF neutralization was investigated with immunohistochemistry. Dual neutralization of paracrine IGF-I and IGF-II showed modest additive antimetastatic effects than single neutralization of IGF-I or IGF-II. In any phase of metastasis, neutralization led to significant tumor growth inhibition and longer survival. Dose escalation of KM1468 influenced survival only in the late phase of metastasis. Apoptosis increased significantly in the antibody-treated group compared with the control group (P = 0.0025) In conclusion, IGFs are promising therapeutic targets for hepatic metastases of colorectal cancers. However, the IGF dependency is probably variable in the metastatic process.     

Two cases of bowel perforation associated with sunitinib treatment for renal cell carcinoma

Sunitinib, a multitargeted tyrosine kinase inhibitor, is widely used in the treatment of carcinoma. Adverse events associated with this treatment, including fatigue, diarrhea, and hematotoxicity, have been reported in clinical trials. Bowel perforation is a surgical emergency that requires immediate treatment depending on the location and progression of the tumor. We report 2 cases of bowel perforation during sunitinib treatment. The patients presented with diffuse peritonitis, and emergency exploratory laparotomy was performed. We speculate that the underlying mechanisms were decrease in capillary density of the normal mucosa in case 1 and tumor shrinkage because of sunitinib treatment in case 2. To the best of our knowledge, this is the first study to report the pathological findings implicating bowel perforation due to sunitinib treatment. Further investigations are needed to clarify the risk factors for intestinal perforations associated with sunitinib treatment.     

Yes is a central mediator of cell growth in malignant mesothelioma cells

The constitutive activation of the Src family kinases (SFKs) has been established as a poor prognostic factor in malignant mesothelioma (MM), however, the family member(s) which contribute to the malignancy have not been defined. This study aimed to identify the SFK member(s) contributing to cell growth using RNA interference in various MM cell lines. Silencing of Yes but not of c-Src or Fyn in MM cells leads to cell growth suppression. This suppressive effect caused by Yes silencing mainly depends on G1 cell cycle arrest and partly the induction of apoptosis. Also, the knockout of Yes induces the inactivation of β-catenin signaling and subsequently decreases the levels of cyclin D necessary for G1-S transition in the cell cycle. In addition, Yes knockout has less effect on cell growth suppression in β-catenin-deficient H28 MM cells compared to other MM cells which express the catenin. Overall, we conclude that Yes is a central mediator for MM cell growth that is not shared with other SFKs such as c-Src.     

Genetic analysis of the susceptibility in rats to aberrant crypt foci formation by 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine, PhIP.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant heterocyclic amine produced while cooking fish and meat, induces aberrant crypt foci (ACF) and colon cancers in rats. We previously reported that F344 rats were sensitive and ACI rats resistant to ACF formation by PhIP, and that the genetic susceptibility in F344 rats to ACF formation by PhIP was autosomally dominant over ACI rats. To identify candidate susceptibility genes in F344 rats, a preliminary genome-wide linkage analysis was employed using a subset of 170 progeny of (F344 x ACI)F1 x ACI backcross rats with either high or low sensitivity to ACF formation by PhIP. Three chromosomes, 1, 6 and 16, demonstrated the presence of loci with a logarithm of the odds (lod) scores of more than 1.0, and a susceptible gene for ACF formation by PhIP was suggested to reside on chromosomes 16.