Advances in cancer biology - metastasis最新文献

The chemokine CX3CL1 emerges as a double-edged sword in the pathophysiology of cancer. We investigated whether CX3CL1 would act as an impediment or as a support to the development of non-small cell lung cancer skeletal metastases.

We set up an in vivo experimental skeletal metastasis model using the LL2 lung cancer cell line expressing low or high levels of CX3CL1. The resulting bone tumors were analyzed using histological, flow cytometry and transcriptomic techniques.

The increased CX3CL1 expression was associated with a strong anti-tumor effect. We observed a significant reduced tumor burden in the high-CX3CL1 group compared to the low-CX3CL1 group with significant differences in the composition of the tumor-infiltrating leukocytes and immunity- and osteogenesis-related gene expression.

Our results highlight the CX3CL1 ability to reduce cancer cell tumorigenicity by potentially disrupting both the vicious cycle linking bone resorption and the tumor cell proliferation as well as by generating an immune permissive tumor microenvironment rich in cancer-fighting immune cells, especially M1 monocytes, B cells and NK cells. In that regard, CX3CL1 could be an interesting tool to increase and/or predict the success of immune-based therapies requiring immune cell trafficking.

Objectives

Tobacco chewing and smoking practices have been a common trend among human populations. Tobacco addiction is a commonly known etiology for oral cancers. The study showcases a clinical case (I_5; a 36y male) with a chronic inflamed persistent oral lesion and positive addiction history of tobacco chewing & smoking to screen out a prognostic target for oral malignancy.

Method

Two-dimensional gel electrophoreses (2DE), using the depleted serum proteome of I_5 and healthy control, were performed for resolving the complex protein repertoire of the secretome. MALDI-TOF-MS and in-silico peptide analyses were used for characterizing the 2DE protein spot of interest. The relative real-time PCR, used for validation of the modulations in the expression of the gene of interest, involved oral cancer (n = 14) and pre-cancer lesions (n = 9). The adjacent normal tissues (encircling oral diseased lesions) and healthy oral epithelia were used as the controls.

Results

The comparative analysis of 2DE profiles uncovered substantial disparities between the depleted secretome of the case (I_5) and the control. The qualitative differential spot ‘a’ (absent in I_5 but present in healthy control) corresponding to HNCUP U2AF26-III was found to down-regulate in the serum proteome of OSCC cases (both tobacco addicts & non-addicts) compared to healthy non-addicts. Also, the expression of the nccpU2AF26 showed significant down-regulation in oral-precancerous and cancerous samples in comparison with the healthy oral epithelia while the expression levels were found to be significantly up-regulated when lesions were compared with their adjacent normal tissues.

Conclusions

The serum proteome of a chronic tobacco addict deficits in multiple proteins constituting the physiological human secretome. The U2AF26-III may function as a prognostic biomarker and therapeutic target for oral malignancies. Also, a non-canonical transcript (nccpU2AF26) lacking exon 3 and 4 was identified to be present in normal oral epithelia and POLs, highlighting the need for rigorous analyses of the role(s) played by U2AF26 non-canonical isoform(s) in the genesis of oral precancer and cancer lesions.

Lung cancer is the second most common cancer worldwide with tobacco being the largest external cause of the disease. Lung cancer is broadly classified into Small Cell Lung Cancer (SCLC) and Non-small-cell Lung Cancer (NSCLC). Depending on the stage of lung cancer, various treatment approaches such as chemotherapy, radiotherapy, surgery, and targeted therapy are in the application. Mutation in Epithelial Growth Factor receptors is a major cause of NSCLC. Variation in downstream genes of EGFR and genes of parallel pathways contributes to NSCLC. The gene that drives tumorigenesis in NSCLC is linked to various pathways like EGRF, ALK, BRAF, MET, ROS1, and RET. This review is an attempt to present a concise view of the reported genetic perturbations behind NSCLC and the approved therapeutic molecules against the disease.

Cutaneous Metastases, a rare clinical manifestation of great importance, arise critical differential diagnostic dilemmas among physicians, as it can easily masquerade into various forms. Besides histological confirmation, a few research has been conducted, concerning imaging and visual magnification techniques, aiming to assess promptly an accurate diagnosis. We review, their benefits and drawbacks, highlighting their necessity to guide histology documentation. Classic imaging techniques have partially served this need so far; nowadays, novel skin imaging methods e.g. Reflectance Confocal Microscopy and Optical Coherence Tomography, as well as dermoscopy, may enlighten these dark diagnostic pathways pioneering effective tools in clinical process. To the best of our knowledge, none of published articles incorporate radiological evaluation and the novel dermoscopic skill in quiver of clinician's diagnostic algorithm concerning Cutaneous Metastases. Herein, we present cumulative data of diagnostic accuracy of imaging and dermoscopic improvements, recommending increasingly their evidence for sufficient CM diagnostic documentation.

Melanoma is the most prevalent and aggressive form of skin cancer, often with a low survival rate due to rapid metastasis and a high occurrence of multi-drug resistance (MDR). In this study, we examine the combination treatment of the recently discovered cytotoxic bacterial metabolite mensacarcin and FDA approved therapeutic vemurafenib (Zelboraf). Vemurafenib is the standard regiment for BRAF V600E mutation positive patients with unresectable or metastatic malignant melanoma. On its own, menscarcin induces mitochondrial dysfunction in selected BRAF-mutant melanoma cell lines. In combination treatment, mensacarcin enhances vemurafenib's cytotoxicity via metabolic impairment. Specifically, it lowers cellular glucose uptake, decreases the oxygen consumption rate, reduces the abundance of glycolytic enzymes, and halts wound healing. Mensacarcin alone retains strong cytotoxic effects in three vemurafenib resistant cell lines SK-Mel-28PLXr, A375PLXr, and A2058PLXr with an average IC₅₀ of 1 μM, inducing apoptosis via the caspase-3/7 pathway. We also find that mensacarcin lowers metastatic migration in a wound healing assay and it alters the morphology of migrating cells on a nanofiber scaffold. Using extracellular matrix (ECM) mimicking fibers, mensacarcin treated cells exhibit a decrease in single cell maximum coil width and an increase in the protrusion length limiting cellular coiling behavior which may limit metastatic migration. In summary, the bacterial metabolite mensacarcin shows great promise as a melanoma drug lead in vitro: in combination with vemurafenib, the cytotoxic activity is enhanced, and alone, mensacarcin retains activity in BRAF inhibitor chemo-resistant melanoma cell lines, and features a unique, migratory limited single cell phenotype.

Comorbid Type 2 diabetes (T2D), a metabolic complication of obesity, associates with worse cancer outcomes for prostate, breast, head and neck, colorectal and several other solid tumors. However, the molecular mechanisms remain poorly understood. Emerging evidence shows that exosomes carry miRNAs in blood that encode the metabolic status of originating tissues and deliver their cargo to target tissues to modulate expression of critical genes. Exosomal communication potentially connects abnormal metabolism to cancer progression. Here, we hypothesized that T2D plasma exosomes induce epithelial-mesenchymal transition (EMT) and immune checkpoints in prostate cancer cells. We demonstrate that plasma exosomes from subjects with T2D induce EMT features in prostate cancer cells and upregulate the checkpoint genes CD274 and CD155. We demonstrate that specific exosomal miRNAs that are differentially abundant in plasma of T2D adults compared to nondiabetic controls (miR374a-5p, miR-93-5p and let-7b-3p) are delivered to cancer cells, thereby regulating critical target genes. We build on our previous reports showing BRD4 controls migration and dissemination of castration-resistant prostate cancer, and transcription of key EMT genes, to show that T2D exosomes require BRD4 to drive EMT and immune ligand expression. We validate our findings with gene set enrichment analysis of human prostate tumor tissue in TGCA genomic data. These results suggest novel, non-invasive approaches to evaluate and potentially block progression of prostate and other cancers in patients with comorbid T2D.

Myocardin is known as an important transcriptional regulator in smooth and cardiac muscle development as well as a tumor suppressor. However, the pathological function of myocardin in NSCLC metastasis is poorly understood. Here, we have described novel roles for myocardin in the metastatic cascade using in vitro and in vivo models. We demonstrate that myocardin deficiency is sufficient to trigger epithelial–mesenchymal transition (EMT) process but reduces metastatic potential of NSCLC in vivo. Myocardin deficiency reduces lung cancer metastasis because of persistent EMT and decreasing colonization capacity. Restoring myocardin expression in colonization stage promotes the metastasis of lung cancer cells. An epigenetically negative feedback loop formed by myocardin and PRMT5/MEP50 complex prevents EMT. We also uncover the unknown mechanism of myocardin suppression in lung cancer tissues that PRMT5/MEP50 complex negatively regulates myocardin expression. It helps to reconcile conflicting results that have challenged the significance of EMT and cancer metastasis and explain the phenotype of myocardin suppression in lung cancer cells.

Treatment failure is one of the main hurdles in treating cervical cancer, despite significant breakthroughs in both conventional and targeted therapy. The one-year survival of patients with advanced or recurrent cervical cancer globally is less than 30%. Chemotherapy, radiation, and concurrent chemoradiotherapy are among the therapeutic modalities being used in clinics, depending on the stage of the disease. However, resistance to these treatment methods compromises the efficacy of the overall treatment. Numerous approaches based on prognostic biomarkers and combination therapy with multiple agents may be able to successfully combat treatment resistance in cervical cancer. In this review, we discuss the molecular mechanisms of treatment resistance in cervical cancer.

Introduction

Intravesical Mycobacterium Bovis bacillus Calmette-Guérin (BCG) therapy for non-muscle invasive bladder cancer has been successfully applied to prevent metastasis and disease progression. However, some studies have reported a percentage of treatment failure and recurrence along with possible side effects. Therefore, this study has evaluated the effect of administration of synthetic (SSeNPs) and biogenic selenium nanoparticles (BSeNPs) as an adjuvant drug in combination with intravesical BCG for the treatment of mice-bearing bladder tumors.

Methods

Orthotopic bladder cancer model mice were established by 12 weeks of N-butyl-N-(4-hydroxybutyl) nitrosamine oral gavage. Mice-bearing bladder cancer was treated by sequential intravesical treatments with SSeNPs, BCG, BCG/SSeNPs, and BCG/SSeNPs. After immunotherapy, the status of the immune system was evaluated by quantitatively measuring mRNA expression of cytokines by Real-time qRT-PCR in the spleen samples and measuring cytokines protein level by enzyme-linked immunosorbent assay in the serum samples. As well, in the tumor microenvironment, the mRNA expression level of autophagic molecules (Beclin-1, ATG2B, and ATG5), apoptotic molecule (Caspase-3), iNOS, HMGB1, and PD-L1 were evaluated in all groups.

Results

Immunotherapy with BCG/SSeNPs and BCG/BSeNPs elicited a considerable immune response by increasing the expression of IFN-γ, IL-12, and IL-6 and inhibiting the expression of IL-10 and TGF-β cytokines. As well, BCG/SSeNPs and BCG/BSeNPs could increase Caspase-3 expression and decrease autophagic genes as well as PD-L1.

Conclusion

Our results showed that synthetic and biogenic SeNPs as an effective adjuvant could enhance intravesical BCG's efficacy and therapeutic effect for bladder cancer treatment with almost the same function.

Prostate cancer (PCa) is considered to be a form of malignancy diagnosed frequently and ranks sixth in instigating death due to cancer in the male population on a global level. Long non-coding RNA (lncRNA) is termed as a type of RNA possessing a length >200 nucleotides. Regardless of the fact that lncRNAs do not code for proteins still, they share various similarities with genes that are protein-coding in nature. Lately, lncRNAs have attained popularity as a pivotal therapeutic target for treating cancer, particularly PCa, primarily as a result of their aberrant expression. The growing demand for finding a permanent cure for PCa has resulted in their overdiagnosis, thereby increasing the chances of utilising lncRNAs as promising diagnostic as well as prognostic markers for effective disease management. The purpose of this review is to revisit and address the studies on the functional role of lncRNAs in PCa management over the past two decades, particularly emphasising recent discoveries with regard to the association of different lncRNAs with PCa, their mechanism of action, assessment of their utility as promising biomarkers and therapeutic candidates, their existing potential applications and prediction of future trends.