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.

Herein we report a first study on single molecular entities bearing both epidermal growth factor receptor (EGFR) and carbonic anhydrase (CA) inhibiting moieties as new tools for the management of hypoxic cancers. Specifically, we designed and synthesized a library of erlotinib (ERL)-based compounds bearing both the primary sulfonamide/coumarin moieties with the intent to selectively interfere with EGFR and CA targets respectively. The compounds obtained were investigated in silico and in vitro for their ability to interact with the appropriate targets followed by the assessment on selected compounds for the anti-proliferative activity using human (h) TNBC cell line MDA-MB-231. We are confident that the data provided in this study are fundamental for paving the way toward the development of multi-targeting molecular structures useful for the management of chronic diseases such as hypoxic tumors.

Background: Sonic hedgehog-medulloblastoma (SHH-MB) represents a biologically diverse and clinically challenging subgroup, especially in high-risk variants characterized by metastatic dissemination. Despite progress in molecular stratification, current treatments rely on intensive multimodal regimens that are associated with substantial long-term neurotoxicity. Identifying novel oncogenic mechanisms that can be therapeutically exploited is therefore a critical priority. Methods: We combined transcriptomic analyses of patient datasets with immunohistochemistry, RNAscope, and protein profiling to evaluate PTX3 expression in MB subgroups. Functional studies were performed in SHH-MB cell lines following PTX3 knockdown or knockout. Effects on proliferation, migration, and angiogenesis were assessed through multiple in vitro assays. In vivo relevance was tested using subcutaneous and orthotopic xenograft models. Mechanistic insights were obtained through phospho-kinase arrays, Western blotting, and GSEA. A high-throughput drug screen and combination studies with specific inhibitors and standard chemotherapy (vincristine/cisplatin/cyclophosphamide; VCC) were performed to assess therapeutic potential. Results: Our results reveal that PTX3 was strongly enriched in SHH-MB subgroup, where it supported proliferation, motility, and angiogenesis. Mechanistically, PTX3 activated a TLR4-dependent IRAK1/PI3K-Akt/GSK-3/β-catenin signaling cascade. Genetic downregulation or pharmacologic blockade of PTX3-TLR4 significantly reduced tumor growth and angiogenesis in vivo. Moreover, the TLR4 inhibitor TAK-242 markedly impacted SHH-MB growth in vitro, and combination therapy of TAK-242 and VCC produced additive/synergistic effects in vitro and significantly prolonged survival in orthotopic SHH-MB-bearing mice. Conclusions: Our findings identify PTX3-TLR4 signaling as key oncogenic driver and a promising therapeutic ­vulnerability in SHH-MB. Targeting this pathway enhances the efficacy of standard therapy and represents a rationale for mechanism-based combination strategies.