Advances in cancer biology - metastasis最新文献

Background

Signal Transducer and Activator of Transcription 3 (STAT3) is an identified critical protein associated with the progression of cancer. Alpha mangostin (α-M), a powerful dietary xanthone found to have anti-cancer properties against various cancers. However, the precise mechanism of its anti-cancer activity is not fully understood. Therefore, the current work hypothesized that targeting STAT3 with α-M inhibits the migration, invasion, and proliferation of breast cancer cells. Firstly, we evaluated the binding affinity of α-M/STAT3 complex using molecular dynamic simulations (MDS) and further we determined the likely underlying mechanism of STAT3 through in-vitro experiments. α-M treatment affected the levels of STAT3 phosphorylation, hnRNP-A1, PKM2, and EMT markers. α-M stimulation in breast cancer cells also resulted in suppressed migratory and invasive behaviour. More importantly, the treatment also affected the Ki67 and BrdU positive cells. In summary, we found the anti-migratory and anti-proliferative actions of α-M in breast cancer cells via STAT3 inhibition. Also, the study significantly adds a new nutraceutical for therapeutic intervention of invasive breast cancer.

Oncoviruses exploit diverse host mechanisms to survive and proliferate. These adaptive strategies overlap with mechanisms employed by malignant cells during their adaptation to dynamic micro-environments and for evasion of immune attack. While the role of individual oncoviruses in mediating cancer progression has been extensively characterized, little is known about the common gene regulatory features of oncovirus-induced cancers. Here, we focus on defining the interplay between several cancer hallmarks, including Epithelial-Mesenchymal Transition (EMT), metabolic alterations, and immune evasion across major oncoviruses by examining publicly available transcriptomics datasets containing both oncovirus-positive and oncovirus-negative samples. We observe that oncovirus-positive samples display varying degrees of EMT and metabolic reprogramming. While the progression of EMT generally associated with an enriched glycolytic metabolic program and suppressed fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS), partial EMT correlated well with glycolysis. Furthermore, oncovirus-positive samples had higher activity and/or expression levels of immune checkpoint molecules, such as PD-L1, which was associated with a partial EMT program. These analyses thus decode common pathways in oncovirus-positive samples that may be used in pinpointing new therapeutic vulnerabilities for cancer cell plasticity.

Pancreatic Ductal Adenocarcinomas (PDAC) is one of the most lethal cancer, shifting it from the fourth highest to the third-highest cause of cancer-related deaths in the United States recently. The majority of the cases are diagnosed when the disease has metastasized and is associated with poor 5-year survival. A long-term survival data of PDAC has not been well reported in the literature. Pancreatic Cancer requires the imminent need of a multidisciplinary approach. The key to an improved long-term outcome involves early diagnosis and curative resection along with chemotherapeutic agents. Gemcitabine has played a positive role as an adjuvant after surgical resection. Regular follow-ups post-resection are mandatory for the detection of neoplastic recurrence. To add to what is already a challenging task, isolated recurrence of PDAC poses greater challenges for the physicians treating the patients because there is no general consensus on how to manage these specific groups of patients. To effectively handle this challenging task, a definite strategy must be adopted. Long-term survival if accomplished must therefore be accompanied by regular follow-up visits including Spiral CT scans and keeping an eye on the serum tumor marker CA19-9, a prognostic survival predictor.

To evaluate a potentially valuable tool to study cancer progression and metastasis, we characterized a novel murine model composed of a parental oncogene-transformed embryonic fibroblast line and five cell lines isolated from progressively advanced tumors. Lines derived from distant metastases displayed significantly greater rates of motility, invasiveness, and extracellular acidification than lines derived from a primary tumor or local metastases. A comprehensive proteomic analysis of these cells showed numerous oncogenes to be upregulated and tumor suppressors to be downregulated in the advanced lines, and provided novel targets for future examination. The first cell line capable of extravasation displayed particularly high proteomic variation, which could provide insight into its epithelial to mesenchymal transition. The proteomic variation was less than that of an established human breast cancer model, indicating that the observed differences are more likely contributive to tumorigenesis. In total, we validated a novel cell model for the study of tumorigenesis, while providing a robust proteomic data set to guide future research.

Thyroid cancer is a common endocrine malignancy with a significant increase in its incidence in the past three decades. Even though research has significantly aided the management of the disease, the progression towards advanced forms of cancers remains indeterminate. In order to investigate the current challenges in thyroid cancer studies, the present work employed systematic and interactive transcriptomic data to construct plausible protein-protein interaction networks to reveal the putative transcriptional control mechanisms in cancer. The data from 4 different datasets consisting of normal samples vs thyroid cancer samples were chosen. Hypoxia being a significant hallmark of cancer was predicted to have a functional role in the progression of cancer. Consequently, prognostic pathways involved in cancer in response to hypoxia were predicted in the present study. The genes from the datasets were intersected with the hypoxia hallmark gene set to detect the significantly differentially expressed genes which were deregulated under the influence of hypoxia. These genes were analyzed by bioinformatic tools and a high correlation was found between 12 significant genes (PLAUR, BGN, SDC2, DUSP1, FOS, EGFR, CP, PPARGC1A, CITED2, RORA, HSPA5 and ACKR3) indicating a significant association between them. Of all the genes PLAUR was found to be novel and it was significantly upregulated under the influence of hypoxia. The hub genes and their role as predicted biomarkers were also determined by ROC curve analysis. This may assist in further research towards understanding role of hypoxia in Thyroid cancer.

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.