Hypoxia‐induced polypoid giant cancer cells in glioma promote the transformation of tumor‐associated macrophages to a tumor‐supportive phenotype

Abstract

Aims: Polypoid giant cancer cells (PGCCs) represent a unique subgroup of stem-like cells, acting as a critical factor in promoting the recurrence of various solid tumors.The effect of PGCCs on the tumor malignancy of glioma and its immune microenvironment remains unclear.Methods: Bioinformatic analysis was performed to investigate the relationship between M2 tumor-associated macrophages (TAMs) infiltration and survival of glioblastoma (GBM) patients. The spatial location of M2 TAMs in GBM was also investigated using the Ivy Glioblastoma Atlas Project (Ivy GAP) database. PGCCs were quantified in glioma of different grades. CoCl 2 was used to induce PGCCs in cultures of A172 cells. PGCCs, and their progeny cells in cultures were further evaluated for morphological features, tumorsphere formation, and TAMs activation. Results:The magnitude of M2 TAMs infiltration is significantly correlated with poor survival in GBM patients. M2 TAMs were enriched in the perinecrotic zone (PNZ) of GBM and positively correlated with hypoxic levels. Increased PGCCs were detected in glioma specimens of higher grades. CoCl 2 induced hypoxia and the transformation of A172 cultures into PGCCs, producing the progeny cells, PGCCs-Dau, through asymmetric division. PGCCs and PGCCs-Dau possessed tumor stem cell-like features, while PGCCs-Dau enhanced the polarization of TAMs into an M2 phenotype with relevance to immunosuppression and malignancy in GBM. Conclusions:PGCCs promote malignancy and immune-suppressive microenvironment in GBM. PGCCs or their progeny cells may be a potential therapeutic target for GBM.

Anti‐cancer effect of targeting fibroblast activation protein alpha in glioblastoma through remodeling macrophage phenotype and suppressing tumor progression

“…The expression of FAP was also strongly positively correlated with the expression of CD206 and CD163, markers of M2‐type macrophages, based on the TCGA dataset (Figure 5F,G, p < 0.001, Pearson's r test). In previous studies, CD68, CD11b, and CD14 are often used to define M0‐type macrophages, while CD206, CD163, and ARG1 are often used to define M2‐type macrophages 17–19 . To better define the cell population, in this study, we used CD68 and CD11b to define M0 macrophages, and CD206 and CD163 to define M2‐type macrophages.…”

“…In previous studies, CD68, CD11b, and CD14 are often used to define M0-type macrophages, while CD206, CD163, and ARG1 are often used to define M2-type macrophages. [17][18][19] To better define the cell population, in this study, we used CD68 and CD11b to define M0 macrophages, and CD206 and CD163 to define M2-type macrophages.…”

What Are the Reasons for Continuing Failures in Cancer Therapy? Are Misleading/Inappropriate Preclinical Assays to Be Blamed? Might Some Modern Therapies Cause More Harm than Benefit?

“…Update: In 2020 we reviewed the literature on the impact of PGCCs on therapy resistance and disease relapse [ 4 ]. Since then, significant progress has been made in this field, including the demonstrations that: increased cellular stiffness, therapy resistance and migratory persistence of PGCCs is driven in part by dysregulation of actin cytoskeletal organization [ 78 ]; hypoxia-induced PGCCs can promote malignancy and an immune-suppressive microenvironment [ 79 ]; autophagy plays a key role in the formation and fate of PGCCs [ 80 , 81 ]; and chemotherapy-induced temporary cell cycle arrest (premature senescence) in cancer cells with differing p53 status can be followed by polyploidization and reprogramming, leading to changes in the expression of genes involved in meiosis and spermatogenesis regulation, resulting in the emergence of descendants that appear to arise inside PGCCs [ 76 ]. There is also recent evidence that mutation in the SF3B1 gene can promote formation of PGCCs in the K562 leukemia cell line [ 82 ].…”

“…There is also recent evidence that mutation in the SF3B1 gene can promote formation of PGCCs in the K562 leukemia cell line [ 82 ]. In addition to numerous research articles (e.g., [ 76 , 78 , 79 , 80 , 81 , 82 ]), in 2022, several comprehensive reviews were published that discussed different aspects of PGCCs in tumorigenesis and therapy resistance across different cancer types (e.g., [ 83 , 84 , 85 , 86 ]).…”

Insights about circadian clock in glioma: From molecular pathways to therapeutic drugs

“…Glioma is characterized as the most aggressive brain tumor type with a median survival period of only 14 months and a 5 years survival rate of less than 10% after diagnosis. 1 , 2 , 3 , 4 Current standard treatment strategies include complete or sub‐complete surgical resection, alkylating agent administration chemotherapy, and radiation therapy. 5 , 6 Alternative treatment can also be applied, including immunotherapy, targeted therapy, and tumor treatment fields (TT fields).…”