Advances in cancer biology - metastasis最新文献

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.

A novel anticancer protein was isolated and purified from the pericarp of Zanthoxylum rhesta, a plant of culinary and ethnomedicinal importance from the Asian subcontinent. The partial purification process was followed by the fast protein liquid chromatography, gel permeation chromatography. This purified protein was obtained as a single band in the SDS-PAGE with molecular mass of 31 kDa and was named as ZRP. It showed anti-angiogenic activity in vivo in Swiss albino mice inoculated with EAC cells indicated by the reduced peritoneal angiogenesis. In ovo CAM assay also showed reduced neoangiogenesis. ZRP accompanied in VEGF reduction due to hindered nuclear translocation of HIF-1α which is a clear evidence of anti-angiogenic potential of the ZRP protein.

The NLRP3 inflammasome is a crucial component in the innate immune response, which regulates the caspase-1 activation for the production of proinflammatory cytokines IL-1 and IL-18. Hence, NLRP3/caspase-1/IL-β1 signaling pathway becomes responsible for the elevation of pathogenesis of several inflammatory disorders like Alzheimer's, cancer, and diabetes mellitus. Multiple molecular and cellular processes, including ionic flux, mitochondrial malfunction, reactive oxygen species generation, and lysosomal damage, have been shown to activate the NLRP3 inflammasome. We report benzophenone integrated derivative-3 (BID-3) as an effective inhibitor of NACHT domain of NLRP3 inflammasome through in silico studies, which involved molecular docking simulations, molecular dynamics simulations, binding free energy calculations as well as druglikeliness and pharmacokinetic analyses. Out of all the BIDs screened, BID-3 was predicted with higher binding efficiency, stability, and druglikeliness potential, in comparison with the MCC950 reference drug used. With the current scenario depicting no complete cure for NLRP3 inactivation, this investigation proves to be an initial breakthrough in the field of pharmacotherapy and drug-discovery. Results obtained from this study could be used as a prominent input for the in vitro and in vivo investigation of pharmacotherapeutic potential of BIDs against the above-mentioned health maladies targeting NLRP3 inflammasome.

Cell-free DNA (cfDNA) are un-encapsulated DNA fragments present in biological fluids ranging in an average size of up to 200 base pairs. The novel use of cfDNA is a prime candidate in the diagnostic and prognostic approach to unveiling many inflammatory diseases, especially cancer. Moreover, their potential as biomarkers is due to their ubiquitous presence in the body, non-invasive nature, and aiding in a different autopsy method. This review will focus on the diagnostic and prognostic potential of cfDNA as non-invasive biomarkers in oncology.

Metastasis is one of the major causes of cancer deaths. However, the mechanisms of cancer cells acquiring aggressiveness and metastatic potential are still under investigation. Although cancer stem cells (CSCs) have been suggested as tumor initiating cells responsible for cancer metastasis, no sufficiently practical models have been found because of less availability of CSCs. We have developed novel CSC models derived from mouse induced pluripotent stem cells (miPSCs) in the presence of conditioned media (CM) from different cancer cell lines. Here, we tried to establish the models of metastasis using three different CSC models, miPS-LLCev, miPS-BT549cm and miPS-Huh7cm cells. The metastatic abilities of these CSC models were evaluated by intraperitoneal injections into mice. The developed metastases were histologically analyzed and the differences in gene expression between parental and metastasized cells were assessed. The expression of CSC and stemness markers was maintained in the cells isolated from metastasis. The three types of CSCs were further analyzed by RNA-sequencing to identify the enriched cytoplasmic signaling pathways. As a result, the three CSC models exhibited different patterns of metastases while the metastasis of miPS-LLCev cells appeared the most aggressive demonstrating hepatocellular carcinoma, which developed from the inside of the liver, as well as pulmonary metastasis. Metastasis related “HIF-1 pathway” was nominated as the candidate of enriched pathway in miPS-LLCev and miPS-Huh7cm cells implying that these CSC models possessed distinguished metastatic potential. Therefore, we concluded that the CSC models developed in this study would provide good models of metastasis linked with the aggressiveness.