Prevent Cancer Progression Research Articles

Debris-stimulated tumor growth: a Pandora's box?

Current cancer therapies aim at eradicating cancer cells from the body. However, killing cells generates cell “debris” which can promote tumor progression. Thus, therapy can be a double-edged sword. Specifically, injury and debris generated by cancer therapies, including chemotherapy, radiation, and surgery, may offset their benefit by promoting the secretion of pro-tumorigenic factors (e.g., eicosanoid-driven cytokines) that stimulate regrowth and metastasis of surviving cells. The debris produced by cytotoxic cancer therapy can also contribute to a tumor microenvironment that promotes tumor progression and recurrence. Although not well understood, several molecular mechanisms have been implicated in debris-stimulated tumor growth that we review here, such as the involvement of extracellular vesicles, exosomal miR-194-5p, Bax, Bak, Smac, HMGB1, cytokines, and caspase-3. We discuss the cases of pancreatic and other cancer types where debris promotes postoperative tumor recurrence and metastasis, thus offering a new opportunity to prevent cancer progression intrinsically linked to treatment by stimulating resolution of tumor-promoting debris.

Age and Cohort Trends of Malignant Melanoma in the United States.

Simple SummaryThe occurrence of melanoma in the United States is increasing over time. We examined trends in melanoma by birth year and age groups to determine if individuals born more recently experience higher rates of melanoma as they age. We examined these trends separately among men and women and by the location on the body that the melanoma occurred. Melanoma incidence has continued to increase across more recent birth years and varies by body site and sex. Melanoma incidence will likely continue to increase as younger individuals age. While these are mostly thin melanomas, treatment to prevent cancer progression is still costly, both economically and emotionally, for patients.The incidence of malignant melanoma in the United States is increasing, possibly due to changes in ultraviolet radiation (UVR) exposure due to lifestyle or increased awareness and diagnosis of melanoma. To determine if more recent birth cohorts experience higher rates of melanoma as they age, we examined age and birth cohort trends in the United States stratified by anatomic site and cancer type (in situ vs. malignant) of the melanoma diagnosed from 1975–2017. Poisson regression of cutaneous melanoma cases per population for 1975–2017 from the Surveillance, Epidemiology, and End Results (SEER) cancer registries was used to estimate age adjusted incidence for five-year birth cohorts restricted to Whites, ages 15–84. The rate of melanoma incidence across birth cohorts varies by anatomic site and sex. Melanomas at all anatomic sites continue to increase, except for head and neck melanomas in men. Much of the increase in malignant melanoma is driven by cases of thin (<1.5 mm) lesions. While increased skin exams may contribute to the increased incidence of in situ and thin melanoma observed across birth cohorts, the shifts in anatomic site of highest melanoma incidence across birth cohorts suggest changes in UVR exposure may also play a role.

Microbiota Alterations in Precancerous Colon Lesions: A Systematic Review.

Simple SummaryEven with recent advances, gut microbiota is still one of the most demanding challenges that research needs to handle. In particular, given its deep impact on gastrointestinal health, microbiota could explain the development and progression of certain diseases. Moreover, it could be used as a potential predictive biomarker. Given this, the relationship between intestinal microbiota and colorectal adenoma, considered a premalignant lesion leading to carcinoma, has been deeply evaluated. This review highlights the historical and novel data on microbiota characteristics in adenoma patients to provide an updated summary of current knowledge and its limits.Gut microbiota plays an important role in human health. It may promote carcinogenesis and is related to several diseases of the gastrointestinal tract. This study of microbial dysbiosis in the etiology of colorectal adenoma aimed to investigate the possible causative role of microbiota in the adenoma–carcinoma sequence and its possible preventive role. A systematic, PRISMA-guided review was performed. The PubMed database was searched using “adenoma microbiota” and selecting original articles between January 2010 and May 2020 independently screened. A higher prevalence of Proteobacteria, Fusobacteria, and Bacteroidetes phyla was observed in the fecal luminal and mucosa-associated microbiota of patients with adenoma. However, other studies provided evidence of depletion of Clostridium, Faecalibacterium, Bacteroides and Romboutsia. Results on the relationship between adenoma endoscopic resection and microbiota were inconsistent. In conclusion, none of the analyzed studies developed a predictive model that could differentiate adenoma from non-adenoma patients, and therefore, to prevent cancer progression. The impact of adenoma’s endoscopic resection on microbiota was investigated, but the results were inconclusive. Further research in the field is required.

Sulforaphane Impact on Reactive Oxygen Species (ROS) in Bladder Carcinoma.

Sulforaphane (SFN) is a natural glucosinolate found in cruciferous vegetables that acts as a chemopreventive agent, but its mechanism of action is not clear. Due to antioxidative mechanisms being thought central in preventing cancer progression, SFN could play a role in oxidative processes. Since redox imbalance with increased levels of reactive oxygen species (ROS) is involved in the initiation and progression of bladder cancer, this mechanism might be involved when chemoresistance occurs. This review summarizes current understanding regarding the influence of SFN on ROS and ROS-related pathways and appraises a possible role of SFN in bladder cancer treatment.

Oleic acid and oleoylethanolamide decrease interferon-γ-induced expression of PD-L1 and induce apoptosis in human lung carcinoma cells

Inhibition of programmed death-ligand 1 (PD-L1) in cancer cells provides a reasonable avenue to prevent cancer progression. Although oleate is known to exert anti-cancer effects, its PD-L1 inhibitory effects have not been proven. This study investigated the effects of oleic acid and an oleic acid metabolite, oleoylethanolamide (OEA), on PD-L1 expression and biomarkers of tumorigenesis in several cancer cell lines, namely A549, HuH-7, MCF-7, DLD-1, and LoVo cells. Specifically, we analyzed the expression of PD-L1 and several apoptosis-related genes using RT-PCR. Interferon-gamma (IFN-γ)-induced modulation of PD-L1 protein expression was investigated using western blotting. Results indicate that IFN-γ stimulation increased the expression of PD-L1 in the chosen cancer cell lines. The IFN-γ-induced expression of PD-L1 was greater in A549 cells, than in other cancerous cell lines. In A549 cells, oleic acid and OEA decreased IFN-γ-induced expression of PD-L1, Bax, Bcl-2, and caspase 3. Oleic acid and OEA decreased IFN-γ-induced phosphorylation of STAT. These results indicate that oleic acid and OEA inhibit PD-1 expression, and induce apoptosis via STAT phosphorylation. Therefore, oleic acid and OEA may prevent cancer formation through STAT phosphorylation with IFN-γ. These findings provide novel insights into the anti-cancer effects of oleic acid-rich oil, such as olive oil.

S100P Interacts with p53 while Pentamidine Inhibits This Interaction.

S100P, a small calcium-binding protein, associates with the p53 protein with micromolar affinity. It has been hypothesized that the oncogenic function of S100P may involve binding-induced inactivation of p53. We used 1H-15N HSQC experiments and molecular modeling to study the molecular interactions between S100P and p53 in the presence and absence of pentamidine. Our experimental analysis indicates that the S100P-53 complex formation is successfully disrupted by pentamidine, since S100P shares the same binding site for p53 and pentamidine. In addition, we showed that pentamidine treatment of ZR-75-1 breast cancer cells resulted in reduced proliferation and increased p53 and p21 protein levels, indicating that pentamidine is an effective antagonist that interferes with the S100P-p53 interaction, leading to re-activation of the p53-21 pathway and inhibition of cancer cell proliferation. Collectively, our findings suggest that blocking the association between S100P and p53 by pentamidine will prevent cancer progression and, therefore, provide a new avenue for cancer therapy by targeting the S100P-p53 interaction.

The Role of Endocannabinoid System in Menopause and Its Related-Diseases

Menopause is a crucial event in women’s health, characterized by the cessation of ovarian function. The estrogens deficiency exposes women to several diseases, including obesity, osteoporosis, cardiovascular diseases and cancer. Menopause-related diseases deeply impact on women’s quality of life and represent a serious public and economic health burden. The Endocannabinoid System (ECS) includes Cannabinoid Type 1 (CB1) and Cannabinoid Type 2 (CB2) receptors, endocannabinoids and all the enzymes involved in their biosynthesis and degradation. It plays a significant role in energy balance, bone metabolism, muscular contractility, vascular tone and cancer progression. CB1 activation is responsible for increasing food intake and body weight, stimulating osteoclast activity, inhibiting oxidative stress and preventing cancer progression. Conversely, the stimulation of CB2 induces a reduction in food intake and in body weight, inhibits osteoclast activity, prevents vascular risk and reduces cancer cells proliferation. Moreover, several polymorphic variants of cannabinoid receptors genes are involved into obesity and osteoporosis. In menopause, the alteration of cannabinoid receptors expression and endocannabinoids levels as well as their role in hormone-related pathways could act a leading role in different pathologies (obesity, osteoporosis, cardiovascular diseases and cancer). Therefore, ECS could be considered a possible prognostic marker and a therapeutic target to oppose the harmful effects of these menopause-related diseases. In this review we aimed to summarize the current state-of-knowledge concerning the impact of ECS on major health issues of postmenopausal women.

Functional role of hub molecules in miRNA and transcription factor mediated gene regulatory network of colorectal and lung cancer

MicroRNAs (miRNAs) have the ability to upregulate and downregulate different biological processes by altering the gene expression at post-transcriptional level which leads to different kinds of diseases including cancer. In this study, we analysed the properties and role of different miRNAs involved in colorectal and lung cancer. The sequence composition characteristics, length distribution, GC percentage comparison for both mature and premature miRNAs and the frequencies of the nucleotides at the seed region of miRNAs were measured. The study showed that purine and pyrimidine bases have a role in upregulation and downregulation of miRNA in cancer. Network analysis of up- and down-regulated miRNAs and their target genes showed hsa-mir-21-5p to be up-regulated in both cancers and targeting the gene PTEN. The co-expressed target gene modules involved in both cancers were also compared. Further, we identified the miRNA targets which are also regulated by the transcription factors. The analysis revealed potential novel miRNA biomarkers such as hsa-miR-106b-5p, hsa-miR-16-5p, hsa-miR-126-3p, hsa-miR-140-5p, hsa-miR-20a-5p, hsa-miR-196a-5p, hsa-miR-17-5p, hsa-miR-95-3p and hsa-miR-146a-5p. The target genes of these miRNAs - CDKN1A, CCND1, VEGFA regulated by a large number of transcription factors, reported as cancer biomarkers. Transcription factors such as SP1, STAT3, TP53 and RE1A regulate a number genes in both lung and colorectal cancers and are reported to be involved in cancer pathways. Thus, the important hub molecules and miRNAs identified here can be modulated to prevent cancer progression and to detect the diseases early.

Pentagalloyl glucose inhibits TNF\u2010\u03b1\u2010activated CXCL1/GRO-\u03b1 expression and induces apoptosis\u2010related genes in triple-negative breast cancer cells

In triple-negative breast cancer (TNBC), the tumor microenvironment is associated with increased proliferation, suppressing apoptotic mechanisms, an altered immune response, and drug resistance. The current investigation was designed to examine the natural compound pentagalloyl glucose (PGG) effects on TNF-α activated TNBC cell lines, MDA-MB-231 and MDA-MB-468. The results obtained showed that PGG reduced the expression of the cytokine GRO-α/CXCL1. PGG also inhibited IƙBKE and MAPK1 genes and the protein expression of IƙBKE and MAPK, indicating that GRO-α downregulation is possibly through NFƙB and MAPK signaling pathway. PGG also inhibited cell proliferation in both cell lines. Moreover, PGG induced apoptosis, modulating caspases, and TNF superfamily receptor genes. It also augmented mRNA of receptors DR4 and DR5 expression, which binds to TNF-related apoptosis-induced ligand, a potent and specific stimulator of apoptosis in tumors. Remarkably, PGG induced a 154-fold increase in TNF expression in MDA-MB-468 compared to a 14.6-fold increase in MDA-MB-231 cells. These findings indicate PGG anti-cancer ability in inhibiting tumor cell proliferation and GRO-α release and inducing apoptosis by increasing TNF and TNF family receptors' expression. Thus, PGG use may be recommended as an adjunct therapy for TNBC to increase chemotherapy effectiveness and prevent cancer progression.

System Xc-: a key regulatory target of ferroptosis in cancer.

Ferroptosis is a type of oxidative stress-dependent regulated necrosis characterized by excessive lipid peroxide accumulation. This novel cell death modality has been implicated in preventing cancer progression. Cancer cells tend to modulate their redox state to prevent excessive peroxidation, eventually facilitating tumor growth. System Xc- (a cystine/glutamate antiporter system) is a promising target in cancer cells for ferroptosis induction. The overexpression of system Xc-, especially its core subunit xCT, has been reported in several tumors, and these high expression levels were closely related to cancer cell proliferation, invasion, metastasis and the tumor microenvironment. xCT might serve as a novel biomarker, and its upregulation almost always indicates drug tolerance and poor survival. Therefore, system Xc- inhibition may enhance chemotherapy sensitivity and optimize patient prognosis. Here, we elaborate on the mediation of ferroptosis by suppressing system Xc- and the relevant underlying molecular mechanism in cancer cells. The spotlight on this approach to cancer treatment is creating a new horizon and pointing to future opportunities.

Snail Overexpression Alters the microRNA Content of Extracellular Vesicles Released from HT29 Colorectal Cancer Cells and Activates Pro-Inflammatory State In Vivo.

Simple SummaryKnowledge of the factors that help migration of carcinoma cells is important for prevention of metastasis. Cancer cells release small particles, extracellular vesicles (EVs) that contain such factors. The aim of this study was to assess if the content of EVs changes through different stages of colorectal cancer (CRC) and evaluate how this process affects cancer progression in vivo in mouse CRC model. We found that EVs released from cells that have migratory properties contain different factors then EVs released from original tumor cells. We also show here that EVs can be incorporated into other cells that facilitate metastasis and change their properties depending on the EVs content. The content of cell-released EVs may also serve as a biomarker that denotes the stage of CRC and may be a target to prevent cancer progression.During metastasis, cancer cells undergo phenotype changes in the epithelial-mesenchymal transition (EMT) process. Extracellular vesicles (EVs) released by cancer cells are the mediators of intercellular communication and play a role in metastatic process. Knowledge of factors that influence the modifications of the pre-metastatic niche for the migrating carcinoma cells is important for prevention of metastasis. We focus here on how cancer progression is affected by EVs released from either epithelial-like HT29-cells or from cells that are in early EMT stage triggered by Snail transcription factor (HT29-Snail). We found that EVs released from HT29-Snail, as compared to HT29-pcDNA cells, have a different microRNA profile. We observed the presence of interstitial pneumonias in the lungs of mice injected with HT29-Snail cells and the percent of mice with lung inflammation was higher after injection of HT29-Snail-EVs. Incorporation of EVs released from HT29-pcDNA, but not released from HT29-Snail, leads to the increased secretion of IL-8 from macrophages. We conclude that Snail modifications of CRC cells towards more invasive phenotype also alter the microRNA cargo of released EVs. The content of cell-released EVs may serve as a biomarker that denotes the stage of CRC and EVs-specific microRNAs may be a target to prevent cancer progression.

The impact of anesthetic techniques on breast cancer recurrence: a systematic review of clinical evidence

Introduction: Surgery is the most effective treatment for breast cancer; however, several factors can impair the immune system during the perioperative period, including the anesthetic technique. Since metastasis is the leading cause of death, one of the treatment pillars is to prevent cancer progression. This systematic review will focus on the prospective clinical evidence available on anesthesia's role in favoring breast cancer recurrence. Methods: The Cochrane Library, Medline, Embase, LILACs, and Web of Science were electronically searched from inception through December 2020 for randomized controlled trials assessing the association of postoperative recurrence and survival with the use of regional anesthesia, opioids, anesthetic adjuncts, and general anesthesia during surgical resection of breast cancer. In total, 711 articles were retrieved. After title and abstract screening and full-text reviews, five randomized controlled trials were selected. Results: Two studies compared inhalation anesthesia with total intravenous anesthesia, while three compared general anesthesia with regional anesthesia and analgesia. There was no significant association between the anesthetic technique and local recurrence, metastasis, or survival. Conclusion: This systematic review did not find an association between the type of anesthesia performed and a higher breast cancer recurrence rate. Up to this time, there is no clinical evidence to support a specific anesthetic technique for malignant breast tumor resection surgeries.

Gene Expression Alterations Associated with Oleuropein-Induced Antiproliferative Effects and S-Phase Cell Cycle Arrest in Triple-Negative Breast Cancer Cells.

It is known that the Mediterranean diet is effective in reducing the risk of several chronic diseases, including cancer. A critical component of the Mediterranean diet is olive oil, and the relationship between olive oil consumption and the reduced risk of cancer has been established. Oleuropein (OL) is the most prominent polyphenol component of olive fruits and leaves. This compound has been shown to have potent properties in various types of cancers, including breast cancer. In the present study, the molecular mechanism of OL was examined in two racially different triple-negative breast cancer (TNBC) cell lines—African American (AA, MDA-MB-468) and Caucasian American (CA, MDA-MB-231). The data obtained showed that OL effectively inhibits cell growth in both cell lines, concomitant with S-phase cell cycle arrest-mediated apoptosis. The results also showed that OL-treated MDA-MB-468 cells were two-fold more sensitive to OL antiproliferative effect than MDA-MB-231 cells were. At lower concentrations, OL modified the expression of many apoptosis-involved genes. OL was more effective in MDA-MB-468, compared to MDA-MB-231 cells, in terms of the number and the fold-change of the altered genes. In MDA-MB-468 cells, OL induced a noticeable transcription activation in fourteen genes, including two members of the caspase family: caspase 1 (CASP1) and caspase 14 (CASP14); two members of the TNF receptor superfamily: Fas-associated via death domain (FADD) and TNF receptor superfamily 21 (TNFRSF21); six other proapoptotic genes: growth arrest and DNA damage-inducible 45 alpha (GADD45A), cytochrome c somatic (CYCS), BCL-2 interacting protein 2 (BNIP2), BCL-2 interacting protein 3 (BNIP3), BH3 interacting domain death agonist (BID), and B-cell lymphoma/leukemia 10 (BCL10); and the CASP8 and FADD-like apoptosis regulator (CFLAR) gene. Moreover, in MDA-MB-468 cells, OL induced a significant upregulation in two antiapoptotic genes: bifunctional apoptosis regulator (BFAR) and B-Raf proto-oncogene (BRAF) and a baculoviral inhibitor of apoptosis (IAP) repeat-containing 3 (BIRC3). On the contrary, in MDA-MB-231 cells, OL showed mixed impacts on gene expression. OL significantly upregulated the mRNA expression of four genes: BIRC3, receptor-interacting serine/threonine kinase 2 (RIPK2), TNF receptor superfamily 10A (TNFRSF10A), and caspase 4 (CASP4). Additionally, another four genes were repressed, including caspase 6 (CASP6), pyrin domain (PYD), and caspase recruitment domain (CARD)-containing (PAYCARD), baculoviral IAP repeat-containing 5 (BIRC5), and the most downregulated TNF receptor superfamily member 11B (TNFRSF11B, 16.34-fold). In conclusion, the data obtained indicate that the two cell lines were markedly different in the anticancer effect and mechanisms of oleuropein’s ability to alter apoptosis-related gene expressions. The results obtained from this study should also guide the potential utilization of oleuropein as an adjunct therapy for TNBC to increase chemotherapy effectiveness and prevent cancer progression.

Role of miRNAs in Sigmoid Colon Cancer: A Search for Potential Biomarkers.

Simple SummaryUnderstanding the microRNAs’ role in cancer is challenging, because, in the most cases, the only tissues available are the tumor and its counterpart, the adjacent-to-tumor tissue. Indeed, this scenario could affect our analyses in the cancer field, including to colorectal cancer. Using systematic criteria to select the healthy individuals and sigmoid colon cancer cases, we found that adjacent-to-tumor tissue already has molecular alterations in relation to healthy tissue and to tumor tissue as well. In addition, all miRNAs found showed to be involved in the carcinogenic process, according to the gene enrichment analysis. We suggested that future cancer studies should consider using these three tissues in their analysis, as well as the creation of a database of healthy individuals’ miRNA expression profiles. Using these three tissues, we could better understand the role of adjacent-to-tissue in cancer and other several questions related with clinical aspects.The aberrant expression of microRNAs in known to play a crucial role in carcinogenesis. Here, we evaluated the miRNA expression profile of sigmoid colon cancer (SCC) compared to adjacent-to-tumor (ADJ) and sigmoid colon healthy (SCH) tissues obtained from colon biopsy extracted from Brazilian patients. Comparisons were performed between each group separately, considering as significant p-values < 0.05 and |Log2(Fold-Change)| > 2. We found 20 differentially expressed miRNAs (DEmiRNAs) in all comparisons, two of which were shared between SCC vs. ADJ and SCC vs. SCH. We used miRTarBase, and miRTargetLink to identify target-genes of the differentially expressed miRNAs, and DAVID and REACTOME databases for gene enrichment analysis. We also used TCGA and GTEx databases to build miRNA-gene regulatory networks and check for the reproducibility in our results. As findings, in addition to previously known miRNAs associated with colorectal cancer, we identified three potential novel biomarkers. We showed that the three types of colon tissue could be clearly distinguished using a panel composed by the 20 DEmiRNAs. Additionally, we found enriched pathways related to the carcinogenic process in which miRNA could be involved, indicating that adjacent-to-tumor tissues may be already altered and cannot be considered as healthy tissues. Overall, we expect that these findings may help in the search for biomarkers to prevent cancer progression or, at least, allow its early detection, however, more studies are needed to confirm our results.

The Roles of Non-Coding RNAs in Tumor-Associated Lymphangiogenesis.

Simple SummaryThe lymphatic system plays key roles in the bodies’ defence against disease, including cancer. The expansion of this system is termed lymphangiogenesis and it is orchestrated by factors and conditions within the microenvironment. One approach to prevent cancer progression is by interfering with these microenvironment factors that promote this process and that facilitate the spread of cancer cells to distant organs. One of these factors are non-coding RNAs. This review will summarize recent findings of the distinct roles played by non-coding RNAs in the lymphatic system within normal tissues and tumours. Understanding the mechanisms involved in this process can provide new avenues for therapeutic intervention for inhibiting the spread of cancer.Lymphatic vessels are regarded as the ”forgotten” circulation. Despite this, growing evidence has shown significant roles for the lymphatic circulation in normal and pathological conditions in humans, including cancers. The dissemination of tumor cells to other organs is often mediated by lymphatic vessels that serve as a conduit and is often referred to as tumor-associated lymphangiogenesis. Some of the most well-studied lymphangiogenic factors that govern tumor lymphangiogenesis are the vascular endothelial growth factor (VEGF-C/D and VEGFR-2/3), neuroplilin-2 (NRP2), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF), to name a few. However, recent findings have illustrated that non-coding RNAs are significantly involved in regulating gene expression in most biological processes, including lymphangiogenesis. In this review, we focus on the regulation of growth factors and non-coding RNAs (ncRNAs) in the lymphatic development in normal and cancer physiology. Then, we discuss the lymphangiogenic factors that necessitate tumor-associated lymphangiogenesis, with regards to ncRNAs in various types of cancer. Understanding the different roles of ncRNAs in regulating lymphatic vasculature in normal and cancer conditions may pave the way towards the development of ncRNA-based anti-lymphangiogenic therapy.

Glycans as Immune Checkpoints: Removal of Branched N-glycans Enhances Immune Recognition Preventing Cancer Progression.

Tumor growth is accompanied with dramatic changes in the cellular glycome, such as the aberrant expression of complex branched N-glycans. However, the role of this protumoral N-glycan in immune evasion and whether its removal contributes to enhancement of immune recognition and to unleashing an antitumor immune response remain elusive. We demonstrated that branched N-glycans are used by colorectal cancer cells to escape immune recognition, instructing the creation of immunosuppressive networks through inhibition of IFNγ. The removal of this "glycan-mask" exposed immunogenic mannose glycans that potentiated immune recognition by DC-SIGN-expressing immune cells, resulting in an effective antitumor immune response. We revealed a glycoimmune checkpoint in colorectal cancer, highlighting the therapeutic efficacy of its deglycosylation to potentiate immune recognition and, thus, improving cancer immunotherapy.

Adjuvant Antitumor Immunity Contributes to the Overall Antitumor Effect of Pegylated Liposomal Doxorubicin (Doxil®) in C26 Tumor-Bearing Immunocompetent Mice.

Doxorubicin (DXR) has been reported to have direct cytotoxicity against cancer cells and indirect immunotoxicity by modulation of host antitumor immunity. Hence, it may prevent cancer progression by a dual mechanism. Doxil®, a formulation of DXR encapsulated in polyethylene glycol modified (PEGylated) liposomes, is the most widely used of the clinically approved liposomal anticancer drugs. However, the effect of Doxil® on host antitumor immunity is not well understood. In this study, Doxil® efficiently suppressed tumor growth in immunocompetent mice bearing C26 murine colorectal carcinomas, but not in T cell-deficient nude mice, indicating a contribution of T cells to the overall antitumor effect of Doxil®. In immunocompetent mice, Doxil® increased major histocompatibility complex (MHC-1) levels in C26 tumors, which may be an indicator of increased immunogenicity of tumor cells, and potentially amplified tumor immunogenicity by decreasing immunosuppressive cells such as regulatory T cells, tumor-associated microphages and myeloid-derived suppressor cells that collectively suppress T cell-mediated antitumor responses. This suggests that encapsulation of DXR into PEGylated liposomes increased the therapeutic efficacy of DXR though effects on host antitumor immunogenicity in addition to direct cytotoxic effects on tumor cells. This report describes the role of host antitumor immunity in the overall therapeutic effects of Doxil®. Manipulating pharmacokinetics and biodistribution of chemotherapeutic agents with immunomodulatory properties may increase their therapeutic efficacies by amplifying host antitumor immunity in addition to direct cytotoxic effects on tumor cells.

Gut microbiota-derived metabolites and colorectal cancer: New insights and updates

Abundant evidence from in-vitro as well as in-vivo studies supports the gut microbiota-derived metabolites as crucial executors of diet effect on the host physiology. As such, a number of microbiota-derived metabolites produced from diet have been connected to complex forms of human diseases such as colorectal cancer (CRC). Despite current unresolved questions concerning molecular mechanisms between metabolites, host signaling pathways, and CRC, some new progresses promise continued advancement of the field. Therefore, clarification of the molecular events underlying which metabolites may regulate proliferation of colonocytes will hopefully open up new avenues for seeking the possibilities affecting host health and exploitation of these capabilities for therapeutic purpose. In this Review, we will discuss recent insights into contributions of the gut microbiota-derived metabolites to CRC and argue that the cumulative effects of metabolites should be considered with the intention of better predict and prevent cancer progression. We will also discuss the signaling pathways induced by specific metabolites toward down-regulation and/or up-regulation of immune system that eventually trigger progression and/or inhibition of CRC.

CRISPR-mediated modification of DNA methylation pattern in the new era of cancer therapy.

In the last 2decades, a wide variety of studies have been conducted on epigenetics and its role in various cancers. A major mechanism of epigenetic regulation is DNA methylation, including aberrant DNA methylation variations such as hypermethylation and hypomethylation in the promoters of critical genes, which are commonly detected in tumors and markthe early stages of cancer development. Therefore, epigenetic therapy has been of special importance in the last decade for cancer treatment. In epigenetic therapy, all efforts are made to modulate gene expression to the normal status. Importantly, recent studies have shownthat epigenetic therapy is focusing on the new gene editing technology, CRISPR-Cas9. This tool was found to be able to effectively modulate gene expression and alter almost any sequencein the genome of cells, resulting in events such as a change in acetylation, methylation, or histone modifications. Of note, the CRISPR-Cas9 system can be used for the treatment of cancers caused by epigenetic alterations. The CRISPR-Cas9 system has greateradvantages than other available methods, including potent activity, easy design andhigh velocity as well as the ability to target any DNA or RNA site. In this review, we described epigenetic modulators, which can be used in the CRISPR-Cas9 system, as well as their functions in gene expression alterations that lead to cancer initiation and progression. In addition, we surveyed various species of CRISPR-dead Cas9 (dCas9) systems, a mutant version of Cas9 with no endonuclease activity. Such systems are applicable in epigenetic therapy for gene expression modulation through chemical group editing on nucleosomes and chromatin remodeling, which finally return the cell to the normal status and prevent cancer progression.

Internal Oligoguanidinium Transporter: Mercury-Free Scalable Synthesis, Improvement of Cellular Localization, Endosomal Escape, Mitochondrial Localization, and Conjugation with Antisense Morpholino for NANOG Inhibition to Induce Chemosensitization of Taxol in MCF-7 Cells.

A nontoxic delivery vehicle is essential for the therapeutic applications of antisense phosphorodiamidate morpholino oligonucleotides (PMOs). Though guanidinium-rich or arginine-rich cellular transporter conjugated Vivo-PMO or PPMO has been developed for in vivo application, however, either their toxicity or stability has become an issue. Previously, we reported nonpeptidic internal guanidinium transporter (IGT) mediated delivery of PMO for gene silencing and got encouraging results. In this paper, we report the synthesis of IGT using a Hg-free method for scale up and N-terminal modification of IGT with a suitable hydrophobic or lipophilic group to improve the cell permeability, endosomal escape, and mitochondrial localization and to reduce toxicity in the MTT assay. For the delivery of PMO, IGT-PMO conjugate was synthesized to target NANOG in cells, a transcription factor required for cancer stem cell proliferation and embryonic development and is involved in many cancers. Our data shows IGT-PMO-facilitated NANOG inhibition, and thereby the prevention of EpCAM-N-Cadherin-Vimentin axis mediated epithelial to mesenchymal transition (EMT) in MCF-7 cells. Moreover, unlike taxol, NANOG inhibition influences the expression of stemness factor c-Myc, Hh-Gli signaling proteins, other cancer related factors, and their respective phenotypes in cancer cells. To the best of our knowledge, this is the first report to illustrate that the IGT-PMO-mediated NANOG inhibition increases the therapeutic potential of taxol and induces G0-G1 arrest in cancer cells to prevent cancer progression. However, it warrants further investigation in other cancer cells and preclinical platforms.