Inhibitors against the p110δ isoform of PI3K have shown remarkable therapeutic efficacy in some human leukaemias1,2. Since p110δ is primarily expressed in leukocytes3, drugs against p110δ have not been considered for the treatment of solid tumours4. We report here that p110δ inactivation in mice protects against a broad range of cancers, including non-haematological solid tumours. We demonstrate that p110δ inactivation in regulatory T cells (Treg) unleashes CD8+ cytotoxic T cells and induces tumour regression. Thus, p110δ inhibitors can break tumour-induced immune tolerance and should be considered for wider use in oncology.

Adiponectin is thought to play a decisive role in the relationships among obesity, insulin resistance and cardiovascular risk. This study investigated whether cardiomyocytes synthesize and secrete adiponectin, and the effects of this hormone on cardiac cells. RT-PCR showed that mouse, rat and human cardiomyocytes produced mRNA for adiponectin and adiponectin receptors 1 and 2. Immunohistochemistry confirmed the presence of adiponectin in the cytoplasm of cultured cardiomyocytes, and radioimmunoassay showed that these cells secreted adiponectin into the culture medium. Exogenous adiponectin enhanced glucose and fatty acid uptake and induced AMPK phosphorylation in cultured cardiomyocytes. Our results demonstrate that adiponectin is synthesized and secreted by isolated murine and human cardiomyocytes, and suggest that the local production of this hormone by cardiomyocytes could be involved in the regulation of cardiac metabolism and function.

The PI3K lipid kinases are involved in signal transduction and intracellular vesicular traffic, endowing these enzymes with multiple cellular functions and important roles in normal physiology and disease. In this mini-review, we aim to distil from the vast PI3K literature the key relevant concepts for successful targeting of this pathway in disease. Of the eight isoforms of PI3K, the class I PI3Ks have been implicated in the aetiology and maintenance of various diseases, most prominently cancer, overgrowth syndromes, thrombosis, inflammation and autoimmunity, with emerging potential roles in metabolic, cardiovascular and other disorders. The development of class I PI3K inhibitors, mainly for use in cancer and inflammatory disorders, is a very active area of drug development. In 2014, an inhibitor of the p110δ isoform of PI3K was approved for the treatment of some human B-cell malignancies. The key therapeutic indications of targeting each class I PI3K isoform are summarized and discussed.

Lysophosphatidylinositol (LPI) is a bioactive lipid generated by phospholipase A2 which is believed to play an important role in several diseases. Indeed LPI can affect various functions such as cell growth, differentiation and motility, in a number of cell-types, including cancer cells, endothelial cells and nervous cells. Despite the fact that LPI-induced cellular functions had been known for more than twenty years, the recent discovery that in several cell-types the orphan G protein-coupled receptor GPR55 acts as the specific receptor for LPI has fuelled novel interest in this lysolipid. Different research groups, including our own, have recently suggested that LPI may be the specific and functional ligand for GPR55, triggering signalling cascades that are relevant to cell proliferation, migration, survival and tumourigenesis. Recently published data suggest that the LPI/GPR55 axis plays an important role in different physiological and pathological contexts. Here we review the available data supporting the role of LPI in cell signalling and the pharmacology of its putative receptor GPR55.

Ghrelin is synthesized and secreted by isolated murine and human cardiomyocytes, probably with paracrine/autocrine effects, and may be involved in protecting these cells from apoptosis.

Background-The ␣ 1 -adrenoceptor-blocking antihypertensive doxazosin has been associated with increased risk of heart failure and is known to induce prostate cell apoptosis. We hypothesized that it might also induce apoptosis in cardiomyocytes. Methods and Results-Hoechst dye vital staining and flow cytometry provided evidence that doxazosin induced apoptosis time-and dose-dependently in cardiomyocytes of the HL-1 cell line. TUNEL assays and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) viability test confirmed that doxazosin induced DNA damage and cell death in these cells. MTT tests showed that doxazosin treatment decreased cell viability in primary cultures of neonatal rat cardiomyocytes, and Hoechst dye vital staining demonstrated doxazosin-induced apoptosis in primary cultures of human adult cardiomyocytes. The proapoptotic effect of doxazosin on cardiomyocytes seems not to depend on ␣ 1 blockade, because it was not modified by cotreatment with ␣-or ␤-adrenergic agonists or with the irreversible ␣ 1 -blocker phenoxybenzamine and because doxazosin also decreased the viability of NIH 3T3 cells, which lack ␣ 1 -adrenoceptors. It also does not involve calcineurin, being unaffected by the presence of the calcineurin inhibitors cyclosporin A and FK506. Three other ␣ 1 -blockers were also investigated; prazosin was proapoptotic, like doxazosin, but 5-methylurapidil and terazosin were not. Conclusions-The ␣ 1 -blockers doxazosin and prazosin induce the apoptosis of cardiomyocytes cultured in vitro by a mechanism that is independent of ␣ 1 blockade and calcineurin.

Mutations in PIK3CA are very frequent in cancer and lead to sustained PI3K pathway activation. The impact of acute expression of mutant PIK3CA during early stages of malignancy is unknown. Using a mouse model to activate the Pik3ca H1047R hotspot mutation in the heterozygous state from its endogenous locus, we here report that mutant Pik3ca induces centrosome amplification in cultured cells (through a pathway involving AKT, ROCK and CDK2/Cyclin E-nucleophosmin) and in mouse tissues, and increased in vitro cellular tolerance to spontaneous genome doubling. We also present evidence that the majority of PIK3CA H1047R mutations in the TCGA breast cancer cohort precede genome doubling. These previously unappreciated roles of PIK3CA mutation show that PI3K signalling can contribute to the generation of irreversible genomic changes in cancer. While this can limit the impact of PI3K-targeted therapies, these findings also open the opportunity for therapeutic approaches aimed at limiting tumour heterogeneity and evolution.

The crosstalk between cancer cells and the tumor microenvironment (TME) is a key determinant of cancer metastasis. Cancer-associated fibroblasts (CAFs), one of the main cellular components of TME, promote cancer cell invasion and dissemination through mechanisms including cell-cell interactions and the paracrine secretion of growth factors, cytokines and chemokines. During metastasis, circulating tumor cells (CTCs) are shed from the primary tumor to the bloodstream, where they can be detected as single cells or clusters. The current knowledge about the biology of CTC clusters positions them as key actors in metastasis formation. It also indicates that CTCs do not act alone and that they may be aided by stromal and immune cells, which seem to shape their metastatic potential. Among these cells, CAFs are found associated with CTCs in heterotypic CTC clusters, and their presence seems to increase their metastatic efficiency. In this review, we summarize the current knowledge on the role that CAFs play on metastasis and we discuss their implication on the biogenesis, metastasis-initiating capacity of CTC clusters, and clinical implications. Moreover, we speculate about possible therapeutic strategies aimed to limit the metastatic potential of CTC clusters involving the targeting of CAFs as well as their difficulties and limitations.