Extracellular Vesicle-Packaged CDH11 and ITGA5 Induce the Premetastatic Niche for Bone Colonization of Breast Cancer Cells.

Although most breast cancer metastases in bone cause osteolytic lesions, the osteogenic niche has commonly been described as an initiator of early-stage bone colonization of disseminated cancer cells. Tumor cell-derived extracellular vesicles (EV) have been shown to determine the organotropism of cancer cells by transferring their cargo, such as nucleic acids and proteins, to resident cells at future metastatic sites and preparing a favorable premetastatic niche. Runt-related transcription factor 2 (RUNX2) and its regulated genes have been shown to facilitate the acquisition of osteomimetic features and to enhance the bone metastatic potential of breast cancer cells. In this study, we present in vivo and in vitro evidence to clarify the role of EVs released by breast cancer cells with high RUNX2 expression in the education of osteoblasts to form an osteogenic premetastatic niche. Furthermore, different extracellular vesicular proteins were identified that mediate events subsequent to the specific recognition of tumor-derived EVs by osteoblasts via cadherin 11 (CDH11) and the induction of the osteogenic premetastatic niche by integrin α5 (ITGA5). CDH11high/ITGA5high EVs were demonstrated to be responsible for the formation of a premetastatic niche that facilitates RUNX2 high-expressing breast cancer cell colonization in bone, revealing a potential EV-based premetastatic niche blockage strategy. SIGNIFICANCE: This study provides mechanistic insights into the generation of an osteogenic premetastatic niche by breast cancer-derived EVs and identifies potential EV-derived diagnostic biomarkers and targets for breast cancer bone metastasis.

Impaired recognition of fear in a Chinese man with bilateral cingulate and unilateral amygdala damage.

LJM, a 41-year-old schizophrenic Chinese man with bilateral anterior cingulate gyrus (Brodmann's area 24) lesions and also a small lesion in right amygdala after an operation, was compared with normal as well as brain-damaged and schizophrenic controls in identification of morphed facial expressions of six basic emotions. In repeated administrations of the test for recognition of facial emotions, over a 1- year period, LJM performed significantly worse for expressions of fear compared with the three groups of controls. Recognition of other emotions was not significantly different from that of the controls, except that his recognition of disgust during the first session (but not in two subsequent sessions) was worse than normal and brain-damaged controls but not worse than schizophrenic controls. The dissociation between recognition of fear and other emotions supported the view that the brain has separable networks for processing different emotions, and that the right amygdala as well as the anterior part of bilateral cingulate gyrus are possible substrates involved in the special network for perception of fear. The results from the various groups of Chinese subjects indicate that they perceive emotions in a categorical manner, and that the six basic emotions are likely to be cross-cultural universals.