Tumor-infiltrating immune cells (TIICs) play essential roles in cancer development and progression. However, the association of TIICs with prognosis in colorectal cancer (CRC) patients remains ...elusive. Infiltration of TIICs was assessed using ssGSEA and CIBERSORT tools. The association of TIICs with prognosis was analyzed in 1,802 CRC data downloaded from the GEO (https://www.ncbi.nlm.nih.gov/geo/) and TCGA (https://portal.gdc.cancer.gov/) databases. Three populations of TIICs, including CD66b+ tumor-associated neutrophils (TANs), FoxP3+ Tregs, and CD163+ tumor-associated macrophages (TAMs) were selected for immunohistochemistry (IHC) validation analysis in 1,008 CRC biopsies, and their influence on clinical features and prognosis of CRC patients was analyzed. Prognostic models were constructed based on the training cohort (359 patients). The models were further tested and verified in testing (249 patients) and validation cohorts (400 patients). Based on ssGSEA and CIBERSORT analysis, the correlation between TIICs and CRC prognosis was inconsistent in different datasets. Moreover, the results with disease-free survival (DFS) and overall survival (OS) data in the same dataset also differed. The high abundance of TIICs found by ssGSEA or CIBERSORT tools can be used for prognostic evaluation effectively. IHC results showed that TANs, Tregs, TAMs were significantly correlated with prognosis in CRC patients and were independent prognostic factors (
≤ 0.001;
≤ 0.023). The prognostic predictive models were constructed based on the numbers of TANs, Tregs, TAMs (C-index
= 0.86; AIC
= 448.43; AIC
= 184.30) and they were more reliable than traditional indicators for evaluating prognosis in CRC patients. Besides, TIICs may affect the response to chemotherapy. In conclusion, TIICs were correlated with clinical features and prognosis in patients with CRC and thus can be used as markers.
Metastasis formation is the major cause of death in most patients with cancer. Despite extensive research, targeting metastatic seeding and colonization is still an unresolved challenge. Only ...recently, attention has been drawn to the fact that metastasizing cancer cells selectively and dynamically adapt their metabolism at every step during the metastatic cascade. Moreover, many metastases display different metabolic traits compared with the tumours from which they originate, enabling survival and growth in the new environment. Consequently, the stage-dependent metabolic traits may provide therapeutic windows for preventing or reducing metastasis, and targeting the new metabolic traits arising in established metastases may allow their eradication.
The Natural Cytotoxicity Receptors (NCRs), NKp46, NKp44, and NKp30, were some of the first human activating Natural Killer (NK) cell receptors involved in the non-MHC-restricted recognition of tumor ...cells to be cloned over 20 years ago. Since this time many host- and pathogen-encoded ligands have been proposed to bind the NCRs and regulate the cytotoxic and cytokine-secreting functions of tissue NK cells. This diverse set of NCR ligands can manifest on the surface of tumor or virus-infected cells or can be secreted extracellularly, suggesting a remarkable NCR polyfunctionality that regulates the activity of NK cells in different tissue compartments during steady state or inflammation. Moreover, the NCRs can also be expressed by other innate and adaptive immune cell subsets under certain tissue conditions potentially conferring NK recognition programs to these cells. Here we review NCR biology in health and disease with particular reference to how this important class of receptors regulates the functions of tissue NK cells as well as confer NK cell recognition patterns to other innate and adaptive lymphocyte subsets. Finally, we highlight how NCR biology is being harnessed for novel therapeutic interventions particularly for enhanced tumor surveillance.
Early diagnosis is pivotal in subsequent prognosis and treatment of cancer. Herein, folic acid-conjugated carbon dots (FA-CDs) as a fluorescent nanoprobe were fabricated for identifying cancer cells ...visually. Green luminescent carbon dots (CDs) from active dry yeast (ADY) were readily prepared in scale-up to reach macroscopic production with a high yield of ~50% via a facile and rapid microwave approach. The as-prepared CDs were further combined with folic acid (FA) by covalent bonding to fabricate the FA-CDs for identification of cancer cells over-expressing folate receptor (FR). Experimental outcomes demonstrated that the resultant FA-CDs noninvasively entered into cancer cells via receptor-mediated endocytosis and could differentiate FR-positive HepG2 cells from a cell mixture by fluorescence imaging, which suggests a promising prospect of the FA-CDs as an efficient probe for cancer diagnosis and succeeding personalized therapy.
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•Green luminescent CDs were prepared using active dry yeast for the first time.•A high yield of ~50% of CDs was achieved for macroscopic production.•CDs were directly modified with FA to fabricate FA-CDs by EDC/NHS reaction.•FA-CDs as probes could effectively identify FR-positive cancer cells from the cell mixture.
Ferroptosis is a recently recognized cell death modality that is morphologically, biochemically and genetically distinct from other forms of cell death and that has emerged to play an important role ...in cancer biology. Recent discoveries have highlighted the metabolic plasticity of cancer cells and have provided intriguing insights into how metabolic rewiring is a critical event for the persistence, dedifferentiation and expansion of cancer cells. In some cases, this metabolic reprogramming has been linked to an acquired sensitivity to ferroptosis, thus opening up new opportunities to treat therapy-insensitive tumours. However, it is not yet clear what metabolic determinants are critical for therapeutic resistance and evasion of immune surveillance. Therefore, a better understanding of the processes that regulate ferroptosis sensitivity should ultimately aid in the discovery of novel therapeutic strategies to improve cancer treatment. In this Perspectives article, we provide an overview of the known mechanisms that regulate sensitivity to ferroptosis in cancer cells and how the modulation of metabolic pathways controlling ferroptosis might reshape the tumour niche, leading to an immunosuppressive microenvironment that promotes tumour growth and progression.
The past several years have seen dramatic leaps in our understanding of how gene expression is rewired at the translation level during tumorigenesis to support the transformed phenotype. This work ...has been driven by an explosion in technological advances and is revealing previously unimagined regulatory mechanisms that dictate functional expression of the cancer genome. In this Review we discuss emerging trends and exciting new discoveries that reveal how this translational circuitry contributes to specific aspects of tumorigenesis and cancer cell function, with a particular focus on recent insights into the role of translational control in the adaptive response to oncogenic stress conditions.
Recent research revealed that doxorubicin (DOX) decreased expression of programmed death-ligand 1 (PD-L1) in cancer cells. However, the detailed mechanisms underlying this effect are not well ...established. Here, we demonstrate that doxorubicin down-regulates PD-L1 expression through induction of AU-rich element (ARE) binding protein tristetraprolin (TTP) in cancer cells. PD-L1 mRNA contain three AREs within its 3′UTR. Doxorubicin induced expression of TTP, increased TTP binding to the 3rd ARE of the PD-L1 3′UTR, and increased decay of PD-L1 mRNA. Inhibition of TTP abrogates the inhibitory effect of doxorubicin on PD-L1 expression. Our data suggest that TTP plays a key role in doxorubicin-mediated down-regulation of PD-L1 by enhancing degradation of PD-L1 mRNA in cancer cells.
•PD-L1 expression showed negative correlation with TTP in cancer cells.•PD-L1 mRNA 3′UTR contained three AU-rich elements (AREs).•Doxorubicin induced TTP expression in cancer cells.•TTP bound to the 3rd ARE within the PD-L1 3′UTR and enhance decay of PD-L1 mRNA.•Inhibition of TTP by siRNA abrogated the inhibitory effect of doxorubicin on PD-L1 expression.
Persistent cancer cells are the discrete and usually undetected cells that survive cancer drug treatment and constitute a major cause of treatment failure. These cells are characterized by their slow ...proliferation, highly flexible energy consumption, adaptation to their microenvironment, and phenotypic plasticity. Mechanisms that underlie their persistence offer highly coveted and sought-after therapeutic targets, and include diverse epigenetic, transcriptional, and translational regulatory processes, as well as complex cell-cell interactions. Although the successful clinical targeting of persistent cancer cells remains to be realized, immense progress has been made in understanding their persistence, yielding promising preclinical results.
Like antibiotic-resistant bacteria, some cancer cells can survive drug treatment and regrow tumors, causing treatment failure. Shen et al. describe the features of persistent cancer cells and avenues for targeting these evasive cells.
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