Advances in cancer biology - metastasis最新文献

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.

Background

In advanced epithelial ovarian cancer (EOC), the peritoneum is the primary site of disease recurrence which occurs in >75% of patients despite complete cytoreductive surgery (CRS) and chemotherapy. Macroscopically undetectable remaining cancer cells are deemed to be a source for recurrent disease. We investigated characteristics of occult disease in biopsies of macroscopically normal peritoneum during CRS.

Materials and methods

We included 14 patients with advanced stage high grade serous ovarian cancer (HGSOC). Eleven patients had received neoadjuvant chemotherapy (NACT) and three patients were chemotherapy naïve. Each patient underwent three study-related peritoneal biopsies: 1) of a metastasis, 2) adjacent to a metastasis and 3) at distance from metastases. Cryostat sections were immunohistochemically stained for PAX8 and PanCK as markers of EOC cells and for CD31 as a marker for vascular and lymphatic endothelium. The sections were analyzed semi-quantitatively.

Results

Macroscopically normal peritoneum showed solitary PAX8-positive cells adjacent to and at distance from metastases in all patients. Thirteen percent of these PAX8-positive cells were found to be attached to the mesothelium and are presumably spread through intra-abdominal fluid. Eighty-seven percent of the solitary PAX8-positive cells were found in the stroma underneath the mesothelium, of which 59% were firmly attached to endothelium and 33% were found in the stroma. In most cases, no sign of proliferation of the solitary cells was observed. Only a few clusters of PAX8-positive cells were found. Chemotherapy did not affect these results.

Conclusions

Solitary PAX8-positive cells are present in the macroscopically healthy-looking peritoneum of all EOC patients investigated, irrespective of the distance to macroscopically-visible metastases and of previous treatment. The majority of these solitary cancer cells were attached to endothelium of capillaries, venules or lymphatic vessels. Their solitary character and lack of proliferation suggests a dormant state, which could explain why these cells are unaffected by neo-adjuvant chemotherapy.

Metastatic lung cancer is often diagnosed at a late stage and is widely known to metastasize to the liver in the Asian population, but the underlying mechanism still remains unclear. Tumour derived exosomes (TDEs) play an important role in metastasis and its contributions to the development of the pre-metastatic niche formation is of utmost importance. In this study serum, derived tumour exosomes form lung cancer liver metastatic patients showed active incorporation by A549 cells in a concentration and time-dependent manner and induced migratory/invasive properties. Moreover, it was observed that cellular uptake of exosomes was increased during G2/M phase stimulating the cells to enter cell cycle phases leading to cell proliferation. Further, we observed that E-cadherin, beta catenin, VEGFA, CDKN2A and TGFBR2 were differentially expressed in treated A549 cells demonstrating an important role of these TDEs in altering the tumour microenvironment. In vivo model demonstrated an increase in serum SGPT and SGOT levels whereas the histopathological examination showed patches of pneumonitis in lungs and advanced inflammation in the liver. Conclusively, our results depict an undisputable role of these exosomes as key modulators in the formation of the pre-metastatic niche required for the colonization of circulating tumour cells (CTCs) ultimately leading to distant metastasis.

Prostate cancer is the most prevalent cancer in males, and usually, death occurs due to bone metastasis. TGFβ has been shown to play an essential role in the metastasis of prostate cancer cells by promoting epithelial-to-mesenchymal transition (EMT). Hesperetin is known to possess anti-microbial, anti-fungal, antioxidant, and anti-cancer properties and good bioavailability. Therefore, this study investigated the effect of hesperetin on TGFβ-induced cell proliferation and EMT in prostate cancer cells (PC3). Interestingly, we found that hesperetin can significantly inhibit the cell proliferation of PC3 cells and arrest the cells in the S and G2M phases of the cell cycle. The invasion and migration assay results decipher the inhibitory effect of hesperetin on TGFβ-induced invasion and migration of prostate cancer cells. Our results confirmed that hesperetin also acts through the canonical signaling pathway, as we observed a significant decrease in the expression of pSmad3. Hesperetin can inhibit the TGFβ induced EMT by increasing E-cadherin expression and decreasing N-cadherin expression. Hesperetin could modulate the TGFβ induced histone methylation marks. Further investigation is required to understand the role of hesperetin in modulating these marks and thus inhibiting TGFβ-induced EMT. Hence, the results of our study identified the potential of hesperetin to modulate TGFβ-induced cell proliferation and invasion and migration of prostate cancer cells which may help inhibit the metastatic growth of prostate cancer cells.

Since ancient times, Moringa oleifera has been a common vegetable in many nations. It has a large number of phenolic compounds with a diverse range of biological activity. It has anticancer properties that can be exploited to create novel medications for the treatment of various malignancies. The current study was conducted to evaluate the in vitro anticancer activities of M. oleifera leaves extracts. The M. oleifera leaves extracts significantly inhibited cell proliferation in the human cancer cell line A549 in a dose-dependent manner. Morphological studies indicated that the extract of moringa leaves stimulated apoptosis as demonstrated by cell shrinkage, blebbing, chromatin condensation, and nuclear fragmentation. Quantitative RT-PCR analyses of Bax and Bcl-2 showed abnormal expression profiles of these genes under various treatment conditions. This study demonstrates that M. oleifera leaves may have the ability to suppress the growth of cancer cells while also enhancing human health and developing new food ingredients. The phytochemicals from M. oleifera leaves can be employed as the primary medications to cure cancer, according to in vitro studies.

Background

As per facts sheet of WHO, cancer is a leading cause of mortality worldwide accounting nearly 10 million deaths in 2020. However, breast, lung, colon and rectum, prostate, skin and stomach cancers are the six most prevailing cancer across the globe. Out of the aforesaid cancers, breast cancer is the most commonly diagnosed cancer worldwide with 2.26 million cases in 2020.

Summary

Metabolic alterations have been found to be associated with most of the cancers, suggesting that both loss of mitochondrial functioning (Warburg metabolism) as well as gain of mitochondrial functioning (OXPHOS) are contributing factor for cancer progression, invasion and metastasis. Here it is noteworthy that cancer is a heterogeneous mass of the cells and different cell types are having different tactics due to difference in tumor microenvironment, clonal selection, clonal evolution and cancer stem cell formation which resultantly affects the overall therapeutic response of the cancer therapies, chemo-resistance, radio-resistance, cancer stem cell formation, angiogenesis, migratory potential, invasion-metastasis cascade etc. Cancer cells are having a great metabolic plasticity which supports their survival, proliferation, invasion, metastasis and relapse. Variety of metabolic drugs are already in clinical practice for various metabolic disorders and are known for their proven safety and efficacy track record since decades and they have been reported for pleitropic influence on mitochondrial metabolism as well as biogenesis. Similarly, some other emerging pro- and anti-oxidative drugs for mitochondrial reactive oxygen species are also known to modulate mitochondrial functioning by various means. Therefore, present review sheds light on the potential of metabolic drugs and mitochondrial modulators on cancer pathologies and their underlying molecular mechanisms through which they may improve clinical outcomes and prognosis of cancer patients by many folds.