Advances in cancer biology - metastasis最新文献

Cervical cancer (CC) is one of the most frequent cancers in women worldwide. The epithelial-mesenchymal transition (EMT) and the extracellular release of TGF-β are phenomena typically associated with different tumorigenic processes, including tumour cell proliferation and metastatization. Specific human microRNAs (miRNAs; miRs) involved in these tumorigenic processes have been identified, becoming important diagnostic and prognostic markers, and even potential therapeutic targets. In parallel, different studies have also shown that plant miRNAs can mediate a cross-kingdom regulation (CKR) of mammalian genes and modulate host's gene expression under pathological conditions, restoring the regulatory activity of endogenous miRNAs lost in cancer. In our previous studies, the miRNome from Moringa oleifera Lam. (henceforth moringa or mol) has been sequenced, showing the presence of several conserved miRNAs in the plant kingdom, whose ability to differentially regulate proliferation and apoptosis in healthy and cancer cells has been demonstrated. Furthermore, the effects of mol-miR treatment on tumorigenesis and EMT have been proved in liver tumour cells. According to these premises, we here investigated the proteomic profile of CC-derived HeLa cells exposed to a mol-miRNA pool, demonstrating the down-representation of specific factors involved in tumorigenesis. The treatment with plant miRs was able to modulate proteins involved in several biological processes linked to EMT. Furthermore, it reduced the expression of TGF-β and significantly inhibited cell motility, as observed following Scratch test and cell viability measurements, with a significant increase of apoptotic events. In conclusion, our results suggest and pave the way for the development of new potential therapeutic approaches based on CKR mediated by plant miRNAs for contrasting human cervical cancer, even in the form of adjuvants to classic treatments for limiting their side effects.

Objectives

In tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) are known to expedite cancer progression (metastasis). CAF-secreted cytokines confer a survival advantage to circulating tumor stem cells (CTSCs) (indicators of residual-disease) facilitating immune system evasion. Collectively, CAFs serve as “bio-incubator" by providing favourable "soil" for their subsequent growth in the circulation during EMT and are thus considered as an important target in diagnostic and therapeutic applications. Thus, the aim of this study was to check the presence of circulating CAF (cCAFs) in blood of lung cancer patients as a liquid biopsy approach.

Materials and methods

Mononuclear cells isolated from the peripheral blood of non-metastatic lung cancer patients were cultured to confirm the presence of cCAF. CAF-specific marker α-SMA and FAP was used to characterise them using Western blot and real time PCR. Furthermore, correlation between expression of cCAFs and various clinico-pathological parameters were examined.

Results

Cultured MNCs showed the presence of cCAFs which was further confirmed by western blotting. All patients were found positive for the presence of cCAFs (α-SMA expression), while healthy individuals lacked this, being α-SMA negative. Moreover, significant trend was observed between different stages of lung cancer patients (p < 0.014), suggesting its probable role in lung cancer progression.

Conclusion

Thus, cCAFs could be companion biomarker for the early detection of tumors as well as it could be efficient biomarker for the prediction of metastasis. However, validation of cCAFs as robust marker is still required to be tested in a more number of patients. This should be done using more than one marker associated with CAFs for their clinical application, as it has a potential implication to monitor the effectiveness of a specific cancer therapy and disease progression.

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.