Highlights of This Issue

Abstract

Resistance to anti-androgen therapy in prostate cancer (PCa) can occur through increased intratumoral/adrenal production of androgens, overexpression of the androgen receptor (AR), and/or AR mutants that exhibit altered ligand specificity or activate transcription in a ligand-independent manner. Given the diversity of mechanisms that can lead to endocrine therapy resistance, it has been difficult to develop drugs that directly and effectively inhibit AR in advanced disease. However, taking the alternative approach of targeting critical processes downstream of AR, Stice and colleagues demonstrate that inhibition of the AR-regulated cyclin D1-CDK 4/6 signaling axis results in substantial tumor inhibition in the most treatment recalcitrant animal models of PCa. These results suggest that CDK4/6 inhibitors (CDK4/6i) are a viable alternative to taxanes, the current standard of care in endocrine therapy-resistant prostate cancer.Circulating microvesicles (MVs) have been described as important players in cell-to-cell communication and tumor-derived MVs can include potentially oncogenic information in cancers. In plasma of leukemia patients, circulating MVs were shown to carry leukemia specific fusion transcripts. Here, using gene expression profiling it is demonstrated that MVs cargo of leukemic cells encloses oncogenic fusion transcripts and mRNA related to basic functions of leukemic cells. In co-culture with mesenchymal stem cells, MVs transferred to target cells enhanced their proliferation. As carriers of oncogenic protein coding messages, MVs potentially jeopardize cell-directed therapy and facilitate the spread to other compartments of the body.Hypoxia-induced changes in composition and stiffness of the extracellular matrix (ECM) in the tumor microenvironment (TME) are well-established. Ju and colleagues now define the role of hypoxia in the regulation of ECM-binding receptors by analyzing the expression of individual integrin subunits within a large clinical cohort of breast cancer (BCa) patients and a panel of 20 BCa cell lines. Furthermore, it was demonstrated that integrin α5 is required for BCa metastasis to lymph nodes and lungs. In clinical specimens, increased integrin α5 expression correlates with poor prognosis, suggesting that targeting integrin α5 has therapeutic benefit for patients with hypoxic tumors.Tyro3, Axl and Mertk (TAM receptors) have been implicated in human cancers, whereby aberrantly elevated expression and signaling is associated with cancer progression, metastasis, and resistance to targeted therapies. Here, Kasikara and colleagues explore the function of TAMs as phosphatidylserine (PS) sensing receptors and reveal that activation of TAMs by apoptotic cells and Gas6 promotes epithelial cell efferocytosis, AKT-mediated chemoresistance, and up-regulation of PD-L1. TAM-mediated up-regulation of PD-L1 could be partially blocked by PS-targeting antibodies or Annexin V; thus, providing a rationale that PS-targeting, anti-TAMs, and anti-PD1 based therapeutics have merit as combinatorial checkpoint inhibitors.