ABSTRACT
Reliable approaches to identify stem cell mechanisms that mediate aggressive cancer could have great therapeutic value, based on the growing evidence of embryonic signatures in metastatic cancers. However, how to best identify and target stem-like mechanisms aberrantly acquired by cancer cells has been challenging. We harnessed the power of reprogramming to examine GRP78, a chaperone protein generally restricted to the endoplasmic reticulum in normal tissues, but which is expressed on the cell surface of human embryonic stem cells and many cancer types. We have discovered that (1) cell surface GRP78 (sGRP78) is expressed on iPSCs and is important in reprogramming, (2) sGRP78 promotes cellular functions in both pluripotent and breast cancer cells (3) overexpression of GRP78 in breast cancer cells leads to an induction of a CD24-/CD44+ tumor initiating cell (TIC) population (4) sGRP78+ breast cancer cells are enriched for stemness genes and appear to be a subset of TICs (5) sGRP78+ breast cancer cells show an enhanced ability to seed metastatic organ sites in vivo. These collective findings show that GRP78 has important functions in regulating both pluripotency and oncogenesis, and suggest that sGRP78 marks a stem-like population in breast cancer cells that has increased metastatic potential in vivo.
Subject(s)
Cell Differentiation , Cell Self Renewal , Heat-Shock Proteins/metabolism , Neoplastic Stem Cells/metabolism , Animals , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Transformation, Neoplastic , Cellular Reprogramming , Endoplasmic Reticulum Chaperone BiP , Female , HEK293 Cells , Heat-Shock Proteins/antagonists & inhibitors , Heat-Shock Proteins/genetics , Humans , Induced Pluripotent Stem Cells/cytology , Induced Pluripotent Stem Cells/metabolism , Lung Neoplasms/pathology , Lung Neoplasms/secondary , Mice , Mice, Knockout , Neoplastic Stem Cells/cytology , RNA Interference , RNA, Small Interfering/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Transplantation, HeterologousABSTRACT
Eosinophilic annular erythema (EAE) is a rare entity of unknown etiology that is possibly related to a hypersensitivity reaction and presents as annular erythematous plaques with tissue eosinophilia. It is classified as a figurate erythema with a controversial relationship to Wells syndrome (WS) in the literature, where it is generally considered a separate entity or subset based on clinical and histopathologic differences. EAE typically presents with recurrent, erythematous, arcuate, and annular plaques on the trunk and proximal extremities. The course of the disease is often chronic, recurrent, and relapsing. Responses to treatment are variable but are typically best with systemic steroids and antimalarials. We report a patient refractory to other therapies who had a striking response to dapsone.
