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The M2 isoform of pyruvate kinase (PKM2) is highly expressed in most cancer cells, and has been studied extensively as a driver of oncogenic metabolism. In contrast, the role of PKM2 in nontransformed cells is little studied, and nearly nothing is known of its role, if any, in quiescent cells. We show here that endothelial cells express PKM2 almost exclusively over PKM1. In proliferating endothelial cells, PKM2 is required to suppress p53 and maintain cell cycle progression. In sharp contrast, PKM2 has a strikingly different role in quiescent endothelial cells, where inhibition of PKM2 leads to degeneration of tight junctions and barrier function. Mechanistically, PKM2 regulates barrier function independently of its canonical activity as a pyruvate kinase. Instead, PKM2 suppresses NF-kB and its downstream target, the vascular permeability factor angiopoietin 2. As a consequence, loss of endothelial cell PKM2 in vivo predisposes mice to VEGF-induced vascular leak, and to severe bacteremia and death in response to sepsis. Together, these data demonstrate new roles of PKM2 in quiescent cells, and highlight the need for caution in developing cancer therapies that target PKM2., Introduction Endothelial cells (ECs) perform numerous critical functions in vertebrate biology, broadly separated into 2 activities. On the one hand, quiescent ECs line the vascular wall and provide a barrier [...]

Cancer cell dependence on activated oncogenes is therapeutically targeted, but acquired resistance is virtually unavoidable. Here we show that the treatment of addicted melanoma cells with BRAF inhibitors, and of breast cancer cells with HER2-targeted drugs, led to an adaptive rise in neuropilin-1 (NRP1) expression, which is crucial for the onset of acquired resistance to therapy. Moreover, NRP1 levels dictated the efficacy of MET oncogene inhibitors in addicted stomach and lung carcinoma cells. Mechanistically, NRP1 induced a JNK-dependent signaling cascade leading to the upregulation of alternative effector kinases EGFR or IGF1R, which in turn sustained cancer cell growth and mediated acquired resistance to BRAF, HER2, or MET inhibitors. Notably, the combination with NRP1-interfering molecules improved the efficacy of oncogene-targeted drugs and prevented or even reversed the onset of resistance in cancer cells and tumor models. Our study provides the rationale for targeting the NRP1-dependent upregulation of tyrosine kinases, which are responsible for loss of responsiveness to oncogene-targeted therapies., Introduction Precision oncology relies on treating individual tumors with drugs that target their specific vulnerabilities. Cancer cells are often characterized by the constitutive activation of an oncogenic signaling cascade to [...]

Control of cellular metabolism is critical for efficient cell function, although little is known about the interplay between cell subset-specific metabolites in situ, especially in the tumor setting. Here, we determined how a macrophage-specific (M[phi]-specific) metabolite, itaconic acid, can regulate tumor progression in the peritoneum. We show that peritoneal tumors (B16 melanoma or ID8 ovarian carcinoma) elicited a fatty acid oxidation-mediated increase in oxidative phosphorylation (OXPHOS) and glycolysis in peritoneal tissue-resident macrophages (pResM[phi]). Unbiased metabolomics identified itaconic acid, the product of immune-responsive gene 1-mediated (Irg1-mediated) catabolism of mitochondrial c/s-aconitate, among the most highly upregulated metabolites in pResM[phi] of tumor-bearing mice. Administration of lentivirally encoded Irg1 shRNA significantly reduced peritoneal tumors. This resulted in reductions in OXPHOS and OXPHOS-driven production of ROS in pResM[phi] and ROS-mediated MAPK activation in tumor cells. Our findings demonstrate that tumors profoundly alter pResM[phi] metabolism, leading to the production of itaconic acid, which potentiates tumor growth. Monocytes isolated from ovarian carcinoma patients' ascites fluid expressed significantly elevated levels of IRG1. Therefore, IRG1 in pResM[phi] represents a potential therapeutic target for peritoneal tumors., Introduction The peritoneal cavity is a frequent site of tumor development and metastasis. Ovarian epithelial cancer often spreads to the peritoneal cavity and is treated similarly to primary peritoneal cancer [...]

Author(s): Yuki Kagoya [1]; Shinya Tanaka [1, 2]; Tingxi Guo [1, 3]; Mark Anczurowski [1, 3]; Chung-Hsi Wang [1, 3]; Kayoko Saso [1]; Marcus O Butler [1, 3, 4]; Mark [...]

Author(s): Bin Guo [1]; Xinxin Huang [1]; Man Ryul Lee [2]; Sang A Lee [2]; Hal E Broxmeyer (corresponding author) [1] Hematopoietic stem cells (HSCs) quiescently reside in bone marrow [...]

The polyamine metabolic pathway has been considered a rational target for antineoplastic therapy since it was discovered that polyamines are absolute requirements for tumor initiation, growth, and, in some instances, survival. Although several promising preclinical studies have demonstrated the critical nature of polyamines for tumor growth, the clinical success of agents targeting polyamine metabolism have been lacking. In the accompanying article, Bianchi-Smiraglia et al. identify both a new target and new drug that inhibits polyamine biosynthesis, reduces intracellular polyamines, and inhibits the growth of several models of human multiple myeloma. These results are both intriguing and provide promise for moving such a strategy to the clinic., Polyamine metabolism as a target for anticancer therapy Polyamine metabolism is frequently dysregulated in cancer (1) and, as such, represents a rational target for anticancer therapy. Several preclinical studies suggested [...]

Author(s): Anna Azvolinsky [1] [illus. 1] Tom Gajewski's deep dive into the human gut came out of a curious finding 15 years ago in research that had nothing to do [...]

Recent studies have highlighted that splicing patterns are frequently altered in cancer and that mutations in genes encoding spliceosomal proteins, as well as mutations affecting the splicing of key cancer-associated genes, are enriched in cancer. In parallel, there is also accumulating evidence that several molecular subtypes of cancer are highly dependent on splicing function for cell survival. These findings have resulted in a growing interest in targeting splicing catalysis, splicing regulatory proteins, and/or specific key altered splicing events in the treatment of cancer. Here we present strategies that exist and that are in development to target altered dependency on the spliceosome, as well as aberrant splicing, in cancer. These include drugs to target global splicing in cancer subtypes that are preferentially dependent on wild-type splicing for survival, methods to alter post-translational modifications of splicing-regulating proteins, and strategies to modulate pathologic splicing events and protein-RNA interactions in cancer., Author(s): Stanley Chun-Wei Lee [1]; Omar Abdel-Wahab (corresponding author) [1, 2] The majority of genes in the human genome consists of multiple exons interspersed with introns that undergo splicing to [...]

Intercellular signaling via extracellular vesicles (EVs) is an underappreciated modality of cell-cell crosstalk that enables cells to convey packages of complex instructions to specific recipient cells. EVs transmit these instructions through their cargoes of multiple proteins, nucleic acids, and specialized lipids, which are derived from their cells of origin and allow for combinatorial effects upon recipient cells. This Review series brings together the recent progress in our understanding of EV signaling in physiological and pathophysiological conditions, highlighting how certain EVs, particularly exosomes, can promote or regulate infections, host immune responses, development, and various diseases--notably cancer. Given the diverse nature of EVs and their abilities to profoundly modulate host cells, this series puts particular emphasis on the clinical applications of EVs as therapeutics and as diagnostic biomarkers., Introduction Cell-cell communication is an essential component in mammalian development and preservation of homeostasis, ensuring fast and efficient responses to alterations or threats within the environment surrounding host cells. Beyond [...]

Author(s): Heidi Ledford After decades of frustration, efforts to develop antibodies that can ferry drugs into cancer cells - and minimize damage to healthy tissue - are gathering steam. The [...]

Clinical use of the anticancer drug methotrexate can be limited by its high toxicity. It emerges that a diet rich in the amino acid histidine increases the effectiveness of methotrexate treatment and lowers toxicity in mice.Clinical use of the anticancer drug methotrexate can be limited by its high toxicity. It emerges that a diet rich in the amino acid histidine increases the effectiveness of methotrexate treatment and lowers toxicity in mice., Author(s): Christian FrezzaAuthor Affiliations:Histidine metabolism boosts cancer therapy An enzyme cofactor termed folate is required for DNA and protein synthesis. In 1948, it was found[sup.2] that leukaemia is particularly sensitive [...]

Author(s): Cynthia L Sears (corresponding author) [1]; Drew M Pardoll [1] Cancer immunotherapy refers to a spectrum of strategies that empower the patient's own immune system to attack their cancer. [...]

Byline: A. Zeydi Sir, Cancer is a major public-health problem in the world and is the leading cause of death in economically developed countries and the second leading cause of [...]

Byline: S. Saxena, B. Pramod, B. Dayananda, K. Nagaraju Oncologists all over the globe, relentlessly research on methodologies for detection of cancer and precise localization of cancer therapeutics with minimal [...]

Byline: S. Kar, L. Subitha, S. Iswarya Palliative care is an approach that improves the quality of life of patients and their families facing the problems associated with life-threatening illness, [...]

Byline: F. Alam, M. Naim, M. Aziz, N. Yadav Applications of nanotechnology in medicine and cancer are becoming increasingly popular. Common nanomaterials and devices applicable in cancer medicine are classifiable [...]

Byline: S. Maduri Cancer is a manifestation of dysregulated gene function arising from a complex interplay of oncogenes and tumor suppressor genes present in our body. Cancer has been constantly [...]

Byline: S. Mirzaaghaei, H. Akrami, MH. Asadi, H. Mahdiuni Background: Angiogenesis is a vital process in development as well as in tumor metastasis. Therefore, inhibition of tumor angiogenesis may be [...]

Byline: F. Alam, M. Naim, M. Aziz, N. Yadav Here we review the scope of nanotechnology in Medicine and human cancer. The imaging and therapy agents can be co-delivered by [...]