Microenvironment and tumor cell plasticity: An easy way out

An in-tumor genetic screen reveals that the BET bromodomain protein, BRD4, is a potential therapeutic target in ovarian carcinoma

“…The tumor microenvironment plays a major role in the process of tumor progression (24). Thus, screens conducted in an in vitro setting may, in some instances, be blind to certain proteins whose function is required for in vivo tumor cell survival.…”

Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer

“…5 The contribution of hypoxia to a more aggressive, invasive, and metastatic phenotype involves multiple mechanisms, including: promotion of genetic 10 and epigenetic changes; 11 inhibition of apoptosis; 12 a shift to glycolytic metabolism; 13 up-regulation of survival factors; 14 production of enzymes mediating invasiveness; 15 stimulation of angiogenic signals; 15 induction of epithelial to mesenchymal transition (EMT); 16 and preferential location of cancer stem cells to hypoxic subregions. 17 TH-302 (1-Methyl-2-nitro-1H-imidazol-5-yl)methyl N,N 0 -bis(2-bromoethyl)phosphorodiamidate) is a hypoxia-activated prodrug composed of 2-nitroimidazole linked to a brominated analog of isophosphoramide mustard (Br-IPM). 18 The 2-nitroimidazole moiety of TH-302 is a substrate for intracellular 1-electron reductases and, when TH-302 is reduced under hypoxic conditions, Br-IPM is released.…”

Targeting tumor-associated macrophages by anti-tumor Chinese materia medica

“…(5,17,18) Subpopulations of M In in vitro models, M s have been classi ed as proinflammatory, classically activated M s (M1) and antiin ammatory; alternatively activated M s (M2) based on their cell surface phenotypes and secreted cytokines. M1 M s participate in the Th1 in ammatory responses primarily through production of pro-inflammatory mediators and up-regulation of cell surface molecules necessary for antigen presentation to activate Th1 cells and enhance the ability to phagocytose pathogenic material.…”

“…(33) M s are recruited to different areas of the TME and educated toward different phenotypes. (17,18) It has been shown that pancreatic cancer cells could activate M s in vitro to polarize toward an M2-phenotype, through the cytokines IL-4, IL-10 and CCL2. (34,35) This effect was con rmed by in vivo results revealing about 90% of all TAMs to be M2 M s. Accordingly, depletion of M s in vivo resulted in a signi cantly reduction in tumor growth.…”