Elevated lipogenesis in epithelial stem-like cell confers survival advantage in ductal carcinoma in situ of breast cancer.

Upregulation of lipogenesis is a hallmark of cancer and blocking the lipogenic pathway is known to cause tumor cell death by apoptosis. However, the exact role of lipogenesis in tumor initiation is as yet poorly understood. We examined the expression profile of key lipogenic genes in clinical samples of ductal carcinoma in situ (DCIS) of breast cancer and found that these genes were significantly upregulated in DCIS. We also isolated cancer stem-like cells (CSCs) from DCIS.com cell line using cell surface markers (CS24(-)CD44(+)ESA(+)) and found that this cell population has significantly higher tumor-initiating ability to generate DCIS compared with the non-stem-like population. Furthermore, the CSCs showed significantly higher level of expression of all lipogenic genes than the counterpart population from non-tumorigenic breast cancer cell line, MCF10A. Importantly, ectopic expression of SREBP1, the master regulator of lipogenic genes, in MCF10A significantly enhanced lipogenesis in stem-like cells and promoted cell growth as well as mammosphere formation. Moreover, SREBP1 expression significantly increased the ability of cell survival of CSCs from MCF10AT, another cell line that is capable of generating DCIS, in mouse and in cell culture. These results indicate that upregulation of lipogenesis is a pre-requisite for DCIS formation by endowing the ability of cell survival. We have also shown that resveratrol was capable of blocking the lipogenic gene expression in CSCs and significantly suppressed their ability to generate DCIS in animals, which provides us with a strong rationale to use this agent for chemoprevention against DCIS.

Hypoxia-induced Jagged2 promotes breast cancer metastasis and self-renewal of cancer stem-like cells.

Notch signaling is often and aberrantly activated by hypoxia during tumor progression; however, the exact pathological role of hypoxia-induced Notch signaling in tumor metastasis is as yet poorly understood. In this study, we aimed to define the mechanism of Notch-ligand activation by hypoxia in both primary tumor and bone stromal cells in the metastatic niche and to clarify their roles in tumor progression. We have analyzed the expression profiles of various Notch ligands in 779 breast cancer patients in GEO database and found that the expression of Jagged2 among all five ligands is most significantly correlated with the overall- and metastasis-free survival of breast cancer patients. The results of our immunohistochemical (IHC) analysis for Jagged2 in 61 clinical samples also revealed that both Jagged2 and Notch signaling were strongly upregulated at the hypoxic invasive front. Activation of Jagged2 by hypoxia in tumor cells induced EMT and also promoted cell survival in vitro. Notably, a γ-secretase inhibitor significantly blocked Notch-mediated invasion and survival under hypoxia by promoting expression of E-cadherin and inhibiting Akt phosphorylation. Importantly, Jagged2 was also found to be upregulated in bone marrow stroma under hypoxia and promoted the growth of cancer stem-like cells by activating their Notch signaling. Therefore, hypoxia-induced Jagged2 activation in both tumor invasive front and normal bone stroma has a critical role in tumor progression and metastasis, and Jagged2 is considered to be a valuable prognostic marker and may serve as a novel therapeutic target for metastatic breast cancer.

A profile of destructive surgery in Nepal Eye Hospital.

This is a study profile of the patients undergoing destructive surgery in Nepal Eye Hospital over a period of 2 years (2001-2003). The rationale of the study was to know the incidence and causes for destructive surgery (enucleation/evisceration) and the measures to prevent them. Patients admitted in the ward from emergency and outpatients departments for the purpose of enucleation and evisceration were taken into this study. Their visual acuity, slit-lamp examinations, fundus evaluation were done. Most of the patients had no perception of light with painful blind eyes, panophthalmitis, endophthalmitis, staphylomas, crush injuries and malignancies. After a decision made by the surgeons in the round, a full consent was taken for the operation. Evisceration was done for cases with history of ocular infections and the rest were enucleated. Destructive operation was done for (a) saving the other eye, (b) life saving, (c) painful condition and disfigurement. The incidence of destructive surgery in Nepal Eye Hospital was 1.40%. male : female ratio was 1.41:1. The causes for destructive surgery were panophthalmitis (31.71%), painful blind eye (21.95%), endophthalmitis (14.63%), staphyloma (14.63%), retinoblastoma (12.20%) and crush injuries (4.88%). Number of evisceration (73.17%) was higher than enucleation (26.83%) as most of the cases were sequele of corneal ulcer. Enucleation was mostly seen in children and evisceration in adults. Lastly, the incidences of destructive surgery would be minimized by (a) Prompt treatment of corneal ulcers for reducing panophthalmitis (b) pre, intra, and post operative care in intra ocular surgery for reducing endophthalmitis, and (c) genetic counselling (pre marital) for reducing childhood malignancies. Decision for destructive surgery should be a team work rather than a single surgeon's opinion. It should be done under general anaesthesia or retrobulbar block. Precaution must be taken to prevent the appalling tragedy of enucleating the wrong eye by marking above on the eye to be operated or EUA prior to surgery. Last but not the least, there should be fitting of a prosthesis for cosmesis, psychological support and careful follow-up of the healthy eye.