Advances in cancer biology - metastasis最新文献

Cancer nanomedicine is an important medical application in nanotechnology research tools that have special properties such as flexibility, easy modulation, and high targeting efficiency on tumor tissues. The designing of controlled drug delivery at a nanoscale level to target tumor cells is known as the nano-drug delivery system (NDDS). Nanoparticles (NPs) - based NDDS has distinct advantages over traditional pharmaceuticals, including greater stability and biocompatibility, enhanced permeability and retention effect (EPR), and precisely targeted tumor tissue. Near-infrared (NIR) light-responsive NPs utilized for photothermal effects are called photothermal therapy (PTT). PTT is the most significant aspect of nanotechnology to cure tumors because, thermal heat energy directly induces tumor ablation, without any normal cell damage and side effects. Chemotherapy is one of the most efficient strategies for cancer therapy but it has side effects. Cancer immunotherapy aims to reactivate autoimmune responses for fighting cancer cells. Hence, the combination of chemotherapy, PTT, and Immunotherapy can be efficiently achieved to enhance antitumor efficacy. This comprehensive review is mainly focused on the combined therapeutic effects of chemo-PTT (CPTT) and photothermal immunotherapy (PIT) on cancer treatment and metastatic inhibition. Nowadays, a specific combination of CPTT and PIT is one of the most effective methods to treat cancers. Therefore, the combined therapeutic approach has a great potential effect to fight against cancer for tumor regression and metastatic inhibition.

Glioblastoma (GB) is the most aggressive primary tumor of central nervous system, where no efficient therapy has been found so far. This is due to high intra- and inter- tumor heterogeneity, fast invasion and the therapy-resistant subpopulation of GB stem cells and their plasticity. Tumor heterogeneity involves interactions among cancer cells and stromal cells, such as mesenchymal stem cells (MSCs), that are recruited into the tumor microenvironment and migrate to the tumor site. Here, we characterized the impact of kinin receptors on the interaction of MSCs with GB cells which is further enhanced by kinin receptor agonists. Interactions between GB cells and MSCs were studied in two- and three-dimensional co-cultures. Kinin receptor activity was modulated by selective agonists and antagonists to evaluate their influence on cell viability, cell-cell interactions, GB U87 cell invasiveness, and phenotype alterations. Tumor cell invasion was enhanced by the kinin-B2 receptor agonist bradykinin, while it was blocked by B2 receptor antagonists applied in U87 cells monoculture and in co-culture with MSCs. Kinin receptor inhibition correlated with enhanced direct U87/MSC interactions, such as heterotypic fusion, vesicle transfer and entosis. Furthermore, kinin receptor modulation influenced expression of F-actin expression and genes associated with epithelial-to-mesenchymal transition in U87 cells upon U87/MSCs co-cultures. Our data support ongoing investigations of kinin receptor inhibition as an adjuvant approach in GB therapy. MSC impacts on cancer progression need further investigation, as they may have a synergistic effect with kininergic receptor activation.

The bone marrow microenvironment is an anatomical site from which we can learn more. It is important to consider the different molecular mechanisms developed there, to obtain possible therapeutic targets that help prevent relapse and chemoresistance. This review addresses epigenetic mechanisms (DNA methylation, histone modification, miRNAs and lnRNAs) involved in the modulation of the microenvironment, which, in turn, contribute to the acquisition of chemoresistance and relapse. Addressing these aspects can contribute to a better understanding of interactions in the bone marrow, which helps turn chemotherapy into a more personalized treatment that not only evaluates alterations in malignant cells, but also considers epigenetic changes present in non-tumor cells, the release of cytokines and exosomes, as well as cell-cell communication. These interactions are described in different neoplastic diseases of hematological origin.

Ovarian cancer results in more deaths than any other gynecological malignancy, with a 5-year survival of only 30%. It is typically diagnosed after it has spread from the primary site to the secondary site. Exosomes are membrane-bound nanovesicles that play a critical role in tumor biology and metastasis by promoting intercellular communication. Tumor-associated exosome populations are widely acknowledged to be heterogenous, as various cell types and hallmark tumor microenvironment stressors impact exosome synthesis. Ovarian cancer cells metastasize using intraperitoneal fluids that are rich in exosomes, suggesting that these circulating exosomes assist detached cancer cells to maintain invasive phenotypes prior to secondary site invasion. Studies show that tumor-secreted exosomes direct organ-specific colonization by fusing exosome integrins with target cells in a tissue-specific fashion. Exosome signaling molecules (mRNA, miRNA, proteins) are encapsulated by cholesterol-rich membranes, and thus protects biomaterials from enzymatic degradation. Therefore, they represent an ideal system for studying the expression of sensitive proteins and RNA and for future drug delivery vehicles. Proteins and RNA exchanged through exosomes also influence the molecular and mechanical properties of ovarian cancer cells promoting adaptations that contribute to invasive and metastatic cell behavior. Tumor-derived exosomes also interact with stromal cells to alter their molecular profiles, thus promoting the development of a more malignant tumor microenvironment (TME), invasive cell behavior, and cancer progression. This review provides an overview on exosome structure and biogenesis and summarizes recent studies on ovarian cancer exosomes, exosome mediated interactions in the tumor microenvironment, and exosome heterogeneity.

Background

The pattern of Gankyrin expression is dynamic in response to various stimuli; it is known to be upregulated in several types of cancer. Therefore, Gankyrin expression may serve as a novel prognostic marker of clinical importance and also be considered as a potential therapeutic target for the development of drug candidates.

Summary

Gankyrin or PSMD10 is an established oncoprotein and their elevated expressions are reported in several types of cancer. Gankyrin is involved in various biological processes including the transformation of cells followed by carcinogenesis and metastasis. Abnormal expression of Gankyrin has been reported in a variety of cancers including liver, pancreatic, esophageal, cervical, lung, breast, and glioma. Notably, elevated expression of Gankyrin modulates the key signaling pathways such as JNK, PI3K/AKT, and mTOR, avidly involved in the regulation of cell cycle, apoptosis, and cell fate decisions, thus resulting in the process of tumorigenesis and metastasis. Contrastingly, downregulated expression of Gankyrin exerts anticancer effects. Evidently, a number of emerging reports revealed Gankyrin as a potential marker for the early detection of various cancers. Therefore, it is consistent with the notion that Gankyrin is a driver gene that serves not only to initiate the process of carcinogenesis, but also to progress into metastatic phenotype. All of the aforementioned properties of Gankyrin are providing an emerging need to explore it as an early diagnosis marker, prognostic marker, and a potential therapeutic target to develop putative drug candidates to treat various cancer types.

Plumbago zeylanica has been used in the traditional system of medicine from thousands of years owing to its potential therapeutic properties, however the anticancer and anti-metastatic effects are largely unknown against cervical cancer cells. In this study we demonstrated the cytotoxicity activity, inhibition of cell migration, induction of S-phase cell cycle arrest and the down regulation of expression level of epidermal growth factor receptor (EGFR) by ethanol extract of the root of P. zeylanica (ERPZ). The cytotoxicity effects were analyzed by MTT assay the IC₅₀ was determined to be 10.49 ​μg/ml after 72 ​h of incubation. Besides, strong inhibition of wound healing activity was observed at 20 ​μg/ml concentration, where the wound size was reduced to 33%. The ethanol root extract of P. zeylanica also showed significant S-phase cell cycle arrest of 68.9% at 20 ​μg/ml concentration in HeLa cells which was accompanied by the down regulation of EGFR. Ethanol extracts of the root of P. zeylanica (ERPZ) treatment inhibited the growth of cervical cancer cells. The ERPZ arrested cells at the S-phase of the cell cycle. Besides the HRLC-MS analysis of ERPZ identified 15 compounds and among which the five major compounds such as 7,8-dihydroxy-4-methylcoumarin, neodiosmin, diosmetin, hispidulin, and formononetin were reported to possess antioxidant and anticancer activities, could plausibly induce cell death in HeLa cells.

Nowadays, still, the exact etiology of cancer remains to be uncovered. The understanding that cancer results from uncontrolled proliferation of cells does not provide a solution to curing cancer. Although several irreconciliable theories on the cause of cancer have been proposed, none explain the overall complexity of the disease. Yet, there is the remarkable discovery that the Egg Cell’s Genetic Program (ECGP) has the potentiel to produce cancer. Based on this first and only experimental model created in the mid-20th century where cancer can be observed in statu nascendi, I hypothesized that cancer arises from a cell reprogrammed with the ECGP as a plausible model that brings together all the pieces of the cancer puzzle.

Today, the experimental production of induced Pluripotent Stem Cells (iPSC’s) and their differentiated derivatives, together with their risk of cancer formation validated this theory.

This is of prime importance as it opens a non-existing line of research with high potential for the fight against cancer. We can transpose the knowledge of the ECGP to facilitate the study of a selective treatment for cancer. Instead of basing therapeutic strategies on the fate of cancer cells, we should consider the potential of the ECGP to produce cancer as the key factor to devise an effective therapeutic strategy that selectively targets cancer cells. I then propose a non-toxic metabolic approach to treating cancer which, instead of killing cancer cells, gives them respiration.

In children, neuroblastoma seems to be the most frequent form of tumor found in the extracranial region, with a wide range of medical outcomes ranging from reduction of the tumor volume with time to even developing into a metastatic form and death, regardless of treatment. mRNA vaccines have emerged as a potential cancer treatment platform and could be used as a treatment of neuroblastoma as well. mRNA vaccines, whether naked or loaded with a carrier, proficiently express the antigens of the tumor in APCs after the process of immunization which facilitates the stimulation of the APCs and innate immune reaction. The characteristics such as elevated effectiveness, harmless administration, quick expansion abilities, and efficient manufacturing allows the mRNA cancer vaccines outperform other traditional vaccination platforms. This review focuses on the mRNA vaccine for the immunotherapy of neuroblastoma and gives an overview based on the recent literature available.

DEAD-box RNA helicase 3 (DDX3) is a versatile target that is elevated in several cancer cases besides being a validated target for viral infections. RK-33 is a well-known compound that has been used to target DDX3. In the current investigation, we have used several computational methods to discover RK-33 like compounds with greater affinity towards DDX3. Correspondingly, 95 compounds were obtained from PubChem and were subjected to molecular docking studies with DDX3 target (PDB code: 2I4I). The resultant two compounds were subjected to molecular dynamics simulation (MDS) studies to investigate the stabilities of the complex, performed for 100 ns in triplicates (100 ns x 3 ​= ​300 ns). The MDS results have shown that the identified compounds have established stable results during the evolution of the simulation across the triplicates, read according to root mean square deviation (RMSD), radius of gyration (Rg) and root mean square fluctuations (RMSF). Taken together we propose two compounds as alternatives to RK-33 with better binding affinity, stable MDS results and acceptable ADMET properties.

Breast cancer is the most common malignancy in women worldwide. Sixty-five percent of breast cancers are estrogen and/or progesterone receptor positive. Estrogen receptor expression is a prognostic and predictive biomarker of response to endocrine therapy, which consists of the selective estrogen receptor modulator tamoxifen, aromatase inhibitors, and the selective estrogen receptor degrader fulvestrant. Cannabidiol is a phytocannabinoid that is emerging as a potential therapeutic agent. The aim of this study was to investigate the effect of cannabidiol on estrogen receptor-positive and estrogen receptor-negative representative breast cancer cell lines in combination with standard therapeutic agents used in clinical practice. To compare the effects of cannabidiol on breast cancer cell viability, cancer cell lines were exposed to increasing concentrations of cannabidiol. The effects of cannabidiol in combination with the endocrine therapeutics tamoxifen, fulvestrant, and the cyclin-dependent kinase inhibitor palbociclib on breast cancer cell viability were examined. We demonstrated that cannabidiol dose-dependently decreased the viability of all breast cancer cell lines independent of estrogen receptor expression. The addition of cannabidiol to tamoxifen had an additive negative effect on cell viability in ER+ ​in estrogen receptor positive T-47D line. Cannabidiol did not attenuate the effect of standard treatment of hormone receptor-positive breast cancer with fulvestrant and palbociclib. In addition, cannabidiol did not attenuate the effect of standard treatment of triple-negative breast cancer and human epidermal growth factor receptor 2 positive breast cancer cell lines with trastuzumab and cisplatin.