Despite aggressive clinical treatment, recurrence of glioblastoma multiforme (GBM) is unavoidable, and the clinical outcome is still poor. A convincing explanation is the phenotypic transition of GBM cells upon aggressive treatment such as radiotherapy. However, the microenvironmental factors contributing to GBM recurrence after treatment remain unexplored. Here, it is shown that radiation‐treated GBM cells produce soluble intercellular adhesion molecule‐1 (sICAM‐1) which stimulates the infiltration of macrophages, consequently enriching the tumor microenvironment with inflammatory macrophages. Acting as a paracrine factor, tumor‐derived sICAM‐1 induces macrophages to secrete wingless‐type MMTV integration site family, member 3A (WNT3A), which promotes a mesenchymal shift of GBM cells. In addition, blockade of either sICAM‐1 or WNT3A diminishes the harmful effect of radiation on tumor progression. Collectively, the findings indicate that cellular crosstalk between GBM and macrophage through sICAM‐1‐WNT3A oncogenic route is involved in the mesenchymal shift of GBM cells after radiation, and suggest that radiotherapy combined with sICAM‐1 targeted inhibition would improve the clinical outcome of GBM patients.
Colorectal cancer (CRC) has a 5-year survival rate of <10%, as it can metastasize to the lungs and liver. Anticancer drugs and targeted therapies used to treat metastatic colorectal cancer have insufficient therapeutic efficacy and are associated with complications. Therefore, research to develop new targeted therapeutics is necessary. Here, we present a novel discovery that intracellular adhesion molecule-1 (ICAM-1) is a potential therapeutic target to enhance therapeutic effectiveness for CRC. ICAM-1 is an important regulator of cell–cell interactions and recent studies have shown that it promotes malignancy in several carcinomas. However, little is known about its effect on CRC. Therefore, we conducted a study to define the mechanism by which ICAM-1 acts. ICAM-1 is phosphorylated by tyrosine-protein kinase Met (c-MET), and phosphorylated ICAM-1 can interact with SRC to increase SRC activity. Consequently, ICAM-1 may further accelerate SRC signaling, promoting the malignant potential of cancer. In addition, treatment with antibodies targeting ICAM-1 showed excellent therapeutic effects in reducing metastasis and angiogenesis. These findings suggest for the first time that ICAM-1 is an important adapter protein capable of mediating the c-MET-SRC signaling axis. Therefore, ICAM-1 can be used as a novel therapeutic target and a metastatic marker for CRC.
Background The biological function of mesenchymal stem‐like cells (MSLCs), a type of stromal cells, in the regulation of the tumour microenvironment is unclear. Here, we investigated the molecular mechanisms underlying extracellular matrix (ECM) remodelling and crosstalk between MSLCs and glioblastomas (GBMs) in tumour progression. Methods In vitro and in vivo co‐culture systems were used to analyze ECM remodelling and GBM infiltration. In addition, clinical databases, samples from patients with GBM and a xenografted mouse model of GBM were used. Results Previous studies have shown that the survival of patients with GBM from whom MSLCs could be isolated is substantially shorter than that of patients from whom MSLCs could not be isolated. Therefore, we determined the correlation between changes in ECM‐related gene expression in MSLC‐isolatable patients with that in MSLC non‐isolatable patients using gene set enrichment analysis (GSEA). We found that lysyl oxidase (LOX) and COL1A1 expressions increased in MSLCs via GBM‐derived clusters of differentiation 40 ligand (CD40L). Mechanistically, MSLCs are reprogrammed by the CD40L/CD40/NFκB2 signalling axis to build a tumour infiltrative microenvironment involving collagen crosslinking. Importantly, blocking of CD40L by a neutralizing antibody‐suppressed LOX expression and ECM remodelling, decreasing GBM infiltration in mouse xenograft models. Clinically, high expression of CD40L, clusters of differentiation 40 (CD40) and LOX correlated with poor survival in patients with glioma. This indicated that GBM‐educated MSLCs promote GBM infiltration via ECM remodelling in the tumour microenvironment. Conclusion Our findings provide mechanistic insights into the pro‐infiltrative tumour microenvironment produced by GBM‐educated MSLCs and highlight a potential therapeutic target that can be used for suppressing GBM infiltration.
Breast cancer is the most common type of cancer in women, and approximately 70% of all breast cancer patients use endocrine therapy, such as estrogen receptor modulators and aromatase inhibitors. In particular, triple-negative breast cancer (TNBC) remains a major threat due to the lack of targeted treatment options and poor clinical outcomes. Here, we found that GPR110 was highly expressed in TNBC and GPR110 plays a key role in TNBC progression by engaging the RAS signaling pathway (via Gαs activation). High expression of GPR110 promoted EMT and CSC phenotypes in breast cancer. Consequently, our study highlights the critical role of GPR110 as a therapeutic target and inhibition of GPR110 could provide a therapeutic strategy for the treatment of TNBC patients.
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