Among the chemotypes studied for selective inhibition of tumour-associated carbonic anhydrases (CAs), SLC-0111 , a ureido-bearing benzenesulfonamide CA IX inhibitor, displayed promising antiproliferative effects in cancer cells in vitro and in vivo , being in Phase Ib/II clinical development. To explore the structural characteristics required for better discrimination of less conserved regions of the enzyme, we investigate the incorporation of the urea linker into an imidazolidin-2-one cycle, a modification already explored previously for obtaining CA inhibitors. This new library of compounds inhibited potently four different hCAs in the nanomolar range with a different isoform selectivity profile compared to the lead SLC-0111 . Several representative CA IX inhibitors were tested for their efficacy to inhibit the proliferation of glioblastoma, pancreatic, and breast cancer cells expressing CA IX, in hypoxic conditions. Unlike previous literature data on SLC-149 , a structurally related sulphonamide to compounds investigated here, our data reveal that these derivatives possess promising anti-proliferative effects, comparable to those of SLC-0111 .

Macrophages are the most abundant immune cells of the tumor microenvironment (TME) and have multiple important functions in cancer. During tumor growth, both tissue-resident macrophages and newly recruited monocyte-derived macrophages can give rise to tumor-associated macrophages (TAMs), which have been associated with poor prognosis in most cancers. Compelling evidence indicate that the high degree of plasticity of macrophages and their ability to self-renew majorly impact tumor progression and resistance to therapy. In addition, the microenvironmental factors largely affect the metabolism of macrophages and may have a major influence on TAMs proliferation and subsets functions. Thus, understanding the signaling pathways regulating TAMs self-renewal capacity may help to identify promising targets for the development of novel anticancer agents. In this review, we focus on the environmental factors that promote the capacity of macrophages to self-renew and the molecular mechanisms that govern TAMs proliferation. We also highlight the impact of tumor-derived factors on macrophages metabolism and how distinct metabolic pathways affect macrophage self-renewal.

Cell lines have always constituted a good investigation tool for cancer research, allowing scientists to understand the basic mechanisms underlying the complex network of phenomena peculiar to the transforming path from a healthy to cancerous cell. The introduction of CRISPR in everyday laboratory activity and its relative affordability greatly expanded the bench lab weaponry in the daily attempt to better understand tumor biology with the final aim to mitigate cancer’s impact in our lives. In this review, we aim to report how this genome editing technique affected in the in vitro modeling of different aspects of tumor biology, its several declinations, and analyze the advantages and drawbacks of each of them.