Heat shock protein 90-␣ (Hsp90␣) is an intracellular molecular chaperone. However, it can also be secreted with the underlying regulatory mechanism remaining far from clear. Here we show that the secreted Hsp90␣ is a C-terminal truncated form and its secretion is regulated by the C-terminal EEVD motif via interacting with proteins containing tetratricopeptide repeat domains. We also demonstrate that secretion of Hsp90␣ is determined by the phosphorylation status at residue Thr-90, regulated by protein kinase A and protein phosphatase 5. We further demonstrate that the secretion of Hsp90␣ is a prerequisite for its proinvasiveness function and blocking the secreted Hsp90␣ results in significant inhibition of tumor metastasis. Meanwhile, the level of plasma Hsp90␣ is positively correlated with tumor malignancy in clinical cancer patients. In sum, our results reveal the regulatory mechanism of Hsp90␣ secretion, and its function in tumor invasiveness, indicating it can be a promising diagnostic marker for tumor malignancy in clinical application.heat shock protein 90-␣ ͉ extracellular ͉ nonconventional protein secretion ͉ MMP-2 ͉ tumor marker

Exosomes are a subset of extracellular vesicles that carry specific combinations of proteins, nucleic acids, metabolites, and lipids. Mounting evidence suggests that exosomes participate in intercellular communication and act as important molecular vehicles in the regulation of numerous physiological and pathological processes, including cancer development. Exosomes are released by various cell types under both normal and pathological conditions, and they can be found in multiple bodily fluids. Moreover, exosomes carrying a wide variety of important macromolecules provide a window into altered cellular or tissue states. Their presence in biological fluids renders them an attractive, minimally invasive approach for liquid biopsies with potential biomarkers for cancer diagnosis, prediction, and surveillance. Due to their biocompatibility and low immunogenicity and cytotoxicity, exosomes have potential clinical applications in the development of innovative therapeutic approaches. Here, we summarize recent advances in various technologies for exosome isolation for cancer research. We outline the functions of exosomes in regulating tumor metastasis, drug resistance, and immune modulation in the context of cancer development. Finally, we discuss prospects and challenges for the clinical development of exosome-based liquid biopsies and therapeutics.

The exact molecular mechanism of how endostatin inhibits angiogenesis and tumor growth remains uncharacterized. Here, we report that endostatin specifically binds to the cell surface nucleolin with high affinity. Blockage of nucleolin by a neutralizing antibody or knockdown of nucleolin by the RNA interference results in loss of antiendothelial activities of endostatin. Importantly, a neutralizing antinucleolin antibody abrogates the antiangiogenic and antitumor activities of endostatin in vivo. Nucleolin and endostatin are colocalized on the cell surface of endothelial cells of angiogenic blood vessels in the tumor environment. Finally, we found that endostatin is internalized and transported into cell nuclei of endothelial cell via nucleolin. In the nucleus, the phosphorylation of nucleolin, which is critical for cell proliferation, can be inhibited by endostatin. Our studies demonstrate that nucleolin is a novel functional receptor for endostatin, and mediates the antiangiogenic and antitumor activities of endostatin. These findings also provide mechanistic insights of how endostatin specifically inhibits proliferating endothelial cell growth and angiogenesis. IntroductionAngiogenesis, sprouting new blood vessels from existing capillaries, is critical for tumor growth. 1,2 Therefore, antiangiogenic molecules offer new promises as novel therapeutic modalities for the treatment of tumors. Endostatin (ES), a 20-kDa C-terminal globular domain of the collagen XVIII, was originally isolated from the supernatant of a cultured murine hemangioendothelioma cell line for its ability to inhibit tumor angiogenesis. 3 In animal models, tumor dormancy could be induced by repeated administration of ES for several cycles without causing drug resistance. 4 Moreover, low toxicity of ES has been reported in both animal studies and human trials. [4][5][6] ES exhibits potent anti-endothelial cell activities including inhibition of cell proliferation, migration, adhesion, and survival, which are all required for angiogenesis in vivo. 3,[7][8][9][10][11] The exact molecular mechanism of ES still remains an enigma, although a number of ES-binding proteins such as integrins, tropomyosin, glypicans, laminin, and MMP2 have been reported as ES receptors. 9,[12][13][14][15] However, whether these ES receptors are involved in the antitumor function of ES remains elusive. Recently, using DNA gene microarray and proteomic analysis, Huber and colleagues have identified a number of potential intracellular targets of ES (Abdollahi et al 16 ). Nevertheless, several antiangiogenic-related properties of ES remain uncharacterized, and they have raised several critical unexplored issues at the molecular level. These include (1) Why does ES specifically target angiogenic blood vessels but not quiescent blood vessels 17 ? (2) Why does ES specifically inhibit tumor growth and produce little if any toxicity in animal studies and clinical trials 4-6 ? (3) Why are heparin-binding sites required for the angiostatic activities of ES 18 ? To unravel these p...

Pollution by heavy metals limits the area of land available for cultivation of food crops. A potential solution to this problem might lie in the molecular breeding of food crops for phytoremediation that accumulate toxic metals in straw while producing safe and nutritious grains. Here, we identify a rice quantitative trait locus we name cadmium (Cd) accumulation in leaf 1 (CAL1), which encodes a defensin-like protein. CAL1 is expressed preferentially in root exodermis and xylem parenchyma cells. We provide evidence that CAL1 acts by chelating Cd in the cytosol and facilitating Cd secretion to extracellular spaces, hence lowering cytosolic Cd concentration while driving long-distance Cd transport via xylem vessels. CAL1 does not appear to affect Cd accumulation in rice grains or the accumulation of other essential metals, thus providing an efficient molecular tool to breed dual-function rice varieties that produce safe grains while remediating paddy soils.