Recent advances in tumor biology have made remarkable achievements in the development of therapy for metastatic castrate-resistant prostate cancer. These advances reflect a growing appreciation for the role of the tumor microenvironment in promoting prostate cancer progression. Prostate cancer is no longer viewed predominantly as a disease of abnormally proliferating epithelial cells but rather as a disease of complex interactions between prostate cancer epithelial cells (epithelial compartment) and the surrounding tissues (stromal compartment) in which they reside. For example, prostate cancers frequently metastasize to bone, an organ that contains a microenvironment rich in extracellular matrix proteins and stromal cells including hematopoietic cells, osteoblasts, osteoclasts fibroblasts, endothelial cells, adipocytes, immune cells, and mesenchymal stem cells. Multiple signaling pathways provide crosstalk between the epithelial and the stromal compartments to enhance tumor growth, including androgen receptor signaling, tyrosine kinase receptor signaling, and immune surveillance. The rationale to disrupt this “two-compartment” crosstalk has led to the development of drugs that target tumor stromal elements in addition to the cancer epithelial cell.

Advanced prostate cancer carries a poor prognosis and novel therapies are needed. Research has focused on identifying mechanisms that promote angiogenesis and cellular proliferation during prostate cancer progression from the primary tumor to bone—the principal site of prostate cancer metastases. One candidate pathway is the fibroblast growth factor (FGF) axis. Aberrant expression of FGF ligands and FGF receptors leads to constitutive activation of multiple downstream pathways involved in prostate cancer progression including mitogen-activated protein kinase, phosphoinositide 3-kinase, and phospholipase Cγ. The involvement of FGF pathways in multiple mechanisms relevant to prostate tumorigenesis provides a rationale for the therapeutic blockade of this pathway, and two small-molecule tyrosine kinase inhibitors—dovitinib and nintedanib—are currently in phase II clinical development for advanced prostate cancer. Preliminary results from these trials suggest that FGF pathway inhibition represents a promising new strategy to treat castrate-resistant disease. Clin Cancer Res; 19(21); 5856–66. ©2013 AACR.

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Commentary to:miR-210 links hypoxia with cell cycle regulation and is deleted in human epithelial ovarian cancerAntonis Giannakakis, Raphael Sandaltzopoulos, Joel Greshock, Shun Liang, Jia Huang, K...

Liquid biopsies hold potential as minimally invasive sources of tumor biomarkers for diagnosis, prognosis, therapy prediction or disease monitoring. We present an approach for parallel single-object identification of circulating tumor cells (CTCs) and tumor-derived large extracellular vesicles (LEVs) based on automated high-resolution immunofluorescence followed by downstream multiplexed protein profiling. Identification of LEVs >6 µm in size and CTC enumeration was highly correlated, with LEVs being 1.9 times as frequent as CTCs, and additional LEVs were identified in 73% of CTC-negative liquid biopsy samples from metastatic castrate resistant prostate cancer. Imaging mass cytometry (IMC) revealed that 49% of cytokeratin (CK)-positive LEVs and CTCs were EpCAM-negative, while frequently carrying prostate cancer tumor markers including AR, PSA, and PSMA. HSPD1 was shown to be a specific biomarker for tumor derived circulating cells and LEVs. CTCs and LEVs could be discriminated based on size, morphology, DNA load and protein score but not by protein signatures. Protein profiles were overall heterogeneous, and clusters could be identified across object classes. Parallel analysis of CTCs and LEVs confers increased sensitivity for liquid biopsies and expanded specificity with downstream characterization. Combined, it raises the possibility of a more comprehensive assessment of the disease state for precise diagnosis and monitoring.