Long non-coding RNAs (lncRNAs) constitute a group of >200-nucleotide ncRNA molecules. lncRNAs regulate several cell functions, such as proliferation, apoptosis, invasion and metastasis. Meanwhile, ...lncRNAs are abnormally expressed in human malignancies, where they suppress or promote tumor growth. The present study focused on growth arrest-specific transcript 5 (GAS5), a well-known lncRNA that acts as a tumor suppressor but is suppressed in multiple types of cancer, including mammary carcinoma, prostate cancer, colorectal cancer, gastric cancer, melanoma, esophageal squamous cell carcinoma, lung cancer, ovarian cancer, cervical cancer, gliomas, osteosarcoma, pancreatic cancer, bladder cancer, kidney cancer, papillary thyroid carcinoma, neuroblastoma, endometrial cancer and liver cancer. Notably, GAS5 is overexpressed in liver cancer, potentially functioning as an oncogene. In the present study, the diagnostic and therapeutic roles of GAS5 in different tumors were reviewed, with a summary of the potential clinical application of the lncRNA, which may help identify novel study directions for GAS5. Key words: long non-coding RNA, GAS5, tumor suppressor gene, diagnostic biomarker, therapeutic targe
Background The situation of patients developing multiple primary cancers is becoming more frequent and graver. This study investigated the risks of developing second primary cancers that are related ...to first primary cancers, and the interval times of synchronous and metachronous multiple primary cancers. Patients and methods Retrospective data were retrieved from 109,054 patients aged greater than or equai to18 who were diagnosed with a first solid cancer and registered at Siriraj Cancer Center between 1991 and 2015. A two-month period between first- and second- primary cancers was used to differentiate metachronous and synchronous multiple primary cancers. The combinations of subsequent cancers and relative risks (RRs) of having multiple primary cancers versus having single primary cancer for the top-ten first and second primary cancers were examined. The RR was adjusted for age of the first primary cancer. A survival analysis of the time to second-primary-cancer development was performed. Results Multiple primary cancers were found in 1785 (1.63%) patients. Most (70.87%) second primary cancers occurred after 2 months of first breast, skin, colorectal, lung, head and neck, liver, male genital cancer-prostate, thyroid, and female genital cancer-non-uterine cancers, resulting in those cancers being classified as metachronous multiple primary cancer. After adjustment for age at first diagnosis, head and neck cancers had the highest metachronous association with second esophageal cancers (RR, 25.06; 95% CI, 13.41-50.77). Prostate cancer and second colorectal cancer also demonstrated a high metachronous association (RR, 2.00; 95% CI, 1.25-3.05). A strong synchronous association was found between uterine and ovarian cancers (RR, 27.77; 95% CI, 17.97-43.63). The median time from the first uterine cancer to second-cancer development was 55 days. Conclusions The top-ten most frequent multiple primary cancers were the following: breast; liver; head and neck; colorectal; male genital cancer-prostate; skin; female genital cancer-uterine; thyroid; lung; and female genital cancer-non-uterine. Second primary cancers showed specific associations that depended on the first primary cancer. Physicians should be cognizant of the most common combinations and the interval times of metachronous and synchronous multiple primary cancers. Keywords: Cancer registry, Metachronous, Multiple primary cancers, Second primary cancer, Synchronous
Despite marked development in cancer therapies during recent decades, the prognosis for advanced cancer remains poor. The conventional tumor–cell‐centric view of cancer can only explain part of ...cancer progression, and thus a thorough understanding of the tumor microenvironment (TME) is crucial. Among cells within the TME, cancer‐associated fibroblasts (CAFs) are attracting attention as a target for cancer therapy. However, CAFs present a heterogeneous population of cells and more detailed classification of CAFs and investigation of functions of each subset is needed to develop novel CAF‐targeted therapies. In this context, application of newly developed approaches to single‐cell analysis has already made an impact on our understanding of the heterogeneity of CAFs. Here, we review the recent literature on CAF heterogeneity and function, and discuss the possibility of novel therapies targeting CAF subsets.
The conventional tumor–cell‐centric view of cancer can only explain a part of cancer progression, thus understanding of the tumor microenvironment (TME) is crucial. Among cells within the TME, cancer‐associated fibroblasts (CAFs) are attracting attention as a target for cancer therapy. Here, we review the recent literature that has improved our understanding of heterogeneity in CAFs and function of each subset, and discuss the possibility of novel therapies targeting CAF subsets.
Smoking is a well-established cause of lung cancer and there is strong evidence that smoking also increases the risk of several other cancers. Alcohol consumption has been inconsistently associated ...with cancer risk in observational studies. This mendelian randomisation (MR) study sought to investigate associations in support of a causal relationship between smoking and alcohol consumption and 19 site-specific cancers.
We used summary-level data for genetic variants associated with smoking initiation (ever smoked regularly) and alcohol consumption, and the corresponding associations with lung, breast, ovarian, and prostate cancer from genome-wide association studies consortia, including participants of European ancestry. We additionally estimated genetic associations with 19 site-specific cancers among 367,643 individuals of European descent in UK Biobank who were 37 to 73 years of age when recruited from 2006 to 2010. Associations were considered statistically significant at a Bonferroni corrected p-value below 0.0013. Genetic predisposition to smoking initiation was associated with statistically significant higher odds of lung cancer in the International Lung Cancer Consortium (odds ratio OR 1.80; 95% confidence interval CI 1.59-2.03; p = 2.26 × 10-21) and UK Biobank (OR 2.26; 95% CI 1.92-2.65; p = 1.17 × 10-22). Additionally, genetic predisposition to smoking was associated with statistically significant higher odds of cancer of the oesophagus (OR 1.83; 95% CI 1.34-2.49; p = 1.31 × 10-4), cervix (OR 1.55; 95% CI 1.27-1.88; p = 1.24 × 10-5), and bladder (OR 1.40; 95% CI 1.92-2.65; p = 9.40 × 10-5) and with statistically nonsignificant higher odds of head and neck (OR 1.40; 95% CI 1.13-1.74; p = 0.002) and stomach cancer (OR 1.46; 95% CI 1.05-2.03; p = 0.024). In contrast, there was an inverse association between genetic predisposition to smoking and prostate cancer in the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium (OR 0.90; 95% CI 0.83-0.98; p = 0.011) and in UK Biobank (OR 0.90; 95% CI 0.80-1.02; p = 0.104), but the associations did not reach statistical significance. We found no statistically significant association between genetically predicted alcohol consumption and overall cancer (n = 75,037 cases; OR 0.95; 95% CI 0.84-1.07; p = 0.376). Genetically predicted alcohol consumption was statistically significantly associated with lung cancer in the International Lung Cancer Consortium (OR 1.94; 95% CI 1.41-2.68; p = 4.68 × 10-5) but not in UK Biobank (OR 1.12; 95% CI 0.65-1.93; p = 0.686). There was no statistically significant association between alcohol consumption and any other site-specific cancer. The main limitation of this study is that precision was low in some analyses, particularly for analyses of alcohol consumption and site-specific cancers.
Our findings support the well-established relationship between smoking and lung cancer and suggest that smoking may also be a risk factor for cancer of the head and neck, oesophagus, stomach, cervix, and bladder. We found no evidence supporting a relationship between alcohol consumption and overall or site-specific cancer risk.
Cancer is the leading cause of death in China and depicting the cancer pattern of China would provide basic knowhows on how to tackle it more effectively. In this study we have reviewed several ...reports of cancer burden, including the Global cancer statistics 2018 and Cancer statistics in China, 2015, along with the GLOBCAN 2018 online database, to investigate the differences of cancer patterns between China, the United States (USA) and the United Kingdom (UK). An estimated 4.3 million new cancer cases and 2.9 million new cancer deaths occurred in China in 2018. Compared to the USA and UK, China has lower cancer incidence but a 30% and 40% higher cancer mortality than the UK and USA, among which 36.4% of the cancer‐related deaths were from the digestive tract cancers (stomach, liver, and esophagus cancer) and have relatively poorer prognoses. In comparison, the digestive cancer deaths only took up ≤ 5% of the total cancer deaths in either USA or UK. Other reasons for the higher mortality in China may be the low rate of early‐stage cancers at diagnosis and non‐uniformed clinical cancer treatment strategies performed by different regions. China is undergoing the cancer transition stage where the cancer spectrum is changing from developing country to developed country, with a rapidly increase cancer burden of colorectal, prostate, female breast cancers in addition to a high occurrence of infection‐related and digestive cancers. The incidence of westernized lifestyle‐related cancers in China (i.e. colorectal cancer, prostate, bladder cancer) has risen but the incidence of the digestive cancers has decreased from 2000 to 2011. An estimated 40% of the risk factors can be attributed to environmental and lifestyle factors either in China or other developed countries. Tobacco smoking is the single most important carcinogenic risk factor in China, contributing to ~ 24.5% of cancers in males. Chronic infection is another important preventable cancer contributor which is responsible for ~ 17% of cancers. Comprehensive prevention and control strategies in China should include effective tobacco‐control policy, recommendations for healthier lifestyles, along with enlarging the coverage of effective screening, educating, and vaccination programs to better sensitize greater awareness control to the general public.
The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor ...signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer, and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed.
Targeting checkpoints of immune cell activation has been demonstrated to be the most effective approach for activation of anti-tumor immune responses. Cytotoxic T-lymphocyte-associated protein 4 ...(CTLA-4) and programmed cell death protein 1 (PD-1), both inhibitory checkpoints commonly seen on activated T-cells have been found to be the most reliable targets for the treatment of cancer. Six drugs targeting PD-1 or its ligand PD-L1 and one drug targeting CTLA-4 have been approved for treatment of different types of cancers and several others are in advanced stages of development. The drugs when administered as monotherapy had dramatic increase in durable response rates and had manageable safety profile, but more than 50% of patients failed to respond to treatment. Combination of CTLA-4 and PD-1 blockers was then evaluated to increase the response rates in patients, and ipilimumab (anti-CTLA-4) plus nivolumab (anti-PD-1) combination was shown to significantly enhance efficacy in metastatic melanoma patients. Subsequently, ipilimumab plus nivolumab was approved for treatment of metastatic melanoma, advanced renal cell carcinoma and metastatic colorectal cancer with MMR/MSI-H aberrations. The success of combination encouraged multiple clinical studies in other cancer types. Efficacy of the combination has been shown in a number of published studies and is under evaluation in multiple ongoing studies. This review aims to support future research in combination immunotherapy by discussing the basic details of CTLA-4 and PD-1 pathways and the results from clinical studies that evaluated combination of CTLA-4 and PD-1/PD-L1 blockers.
Diabetes treatments were related with either an increased or reduced risk of cancer. There is ongoing debate about a potential protective action of metformin. To summarize evidence on the association ...between metformin and risk of cancer and cancer mortality in patients with diabetes.
MEDLINE and EMBASE (January 1966-April 2012). We selected randomized studies comparing metformin and other hypoglycaemic agents and observational studies exploring the association between exposure to metformin and cancer. Outcomes were cancer mortality, all malignancies and site-specific cancers.
Of 25307 citations identified, 12 randomized controlled trials (21,595 patients) and 41 observational studies (1,029,389 patients) met the inclusion criteria. In observational studies there was a significant association of exposure to metformin with the risk of cancer death 6 studies, 24,410 patients, OR:0.65, 95%CI: 0.53-0.80, all malignancies 18 studies, 561,836 patients, OR:0.73, 95%CI: 0.61-0.88, liver 8 studies, 312,742 patients, OR:0.34; 95%CI: 0.19-0.60 colorectal 12 studies, 871,365 patients, OR:0.83, 95%CI: 0.74-0.92, pancreas 9 studies, 847,248 patients, OR:0.56, 95%CI: 0.36-0.86, stomach 2 studies, 100701 patients, OR:0.83, 95%CI: 0.76-0.91, and esophagus cancer 2 studies, 100694 patients, OR:0.90, 95%CI: 0.83-0.98. No significant difference of risk was observed in randomized trials. Metformin was not associated with the risk of: breast cancer, lung cancer, ovarian cancer, uterus cancer, prostate cancer, bladder cancer, kidney cancer, and melanoma.
Results suggest that Metformin might be associated with a significant reduction in the risk of cancer and cancer-related mortality. Randomized trials specifically designed to evaluate the efficacy of metformin as an anticancer agent are warranted.
Tumor associated macrophages (TAMs) are considered with the capacity to have both negative and positive effects on tumor growth. The prognostic value of TAM for survival in patients with solid tumor ...remains controversial.
We conducted a meta-analysis of 55 studies (n = 8,692 patients) that evaluated the correlation between TAM (detected by immunohistochemistry) and clinical staging, overall survival (OS) and disease free survival (DFS). The impact of M1 and M2 type TAM (n = 5) on survival was also examined.
High density of TAM was significantly associated with late clinical staging in patients with breast cancer risk ratio (RR) = 1.20 (95% confidence interval (CI), 1.14-1.28) and bladder cancer RR = 3.30 (95%CI, 1.56-6.96) and with early clinical staging in patients with ovarian cancer RR = 0.52 (95%CI, 0.35-0.77). Negative effects of TAM on OS was shown in patients with gastric cancer RR = 1.64 (95%CI, 1.24-2.16), breast cancer RR = 8.62 (95%CI, 3.10-23.95), bladder cancer RR = 5.00 (95%CI, 1.98-12.63), ovarian cancer RR = 2.55 (95%CI, 1.60-4.06), oral cancer RR = 2.03 (95%CI, 1.47-2.80) and thyroid cancer RR = 2.72 (95%CI, 1.26-5.86),and positive effects was displayed in patients with colorectal cancer RR = 0.64 (95%CI, 0.43-0.96). No significant effect was showed between TAM and DFS. There was also no significant effect of two phenotypes of TAM on survival.
Although some modest bias cannot be excluded, high density of TAM seems to be associated with worse OS in patients with gastric cancer, urogenital cancer and head and neck cancer, with better OS in patients with colorectal cancer.
PDF
