Among all the stromal cells that present in the tumor microenvironment, cancer-associated fibroblasts (CAFs) are one of the most abundant and critical components of the tumor mesenchyme, which not only provide physical support for tumor cells but also play a key role in promoting and retarding tumorigenesis in a context-dependent manner. CAFs have also been involved in the modulation of many components of the immune system, and recent studies have revealed their roles in immune evasion and poor responses to cancer immunotherapy. In this review, we describe our current understanding of the tumorigenic significance, origin, and heterogeneity of CAFs, as well as the roles of different CAFs subtypes in distinct immune cell types. More importantly, we highlight potential therapeutic strategies that target CAFs to unleash the immune system against the tumor.

Recent studies have demonstrated the importance of non-protein coding part of human genome in carcinogenesis and metastasis. Among numerous kinds of non-protein coding RNAs, long noncoding RNAs (lncRNAs) play a key regulatory role in cancer biology. LncRNAs are dysregulated in different kinds of cancer and the expression levels of certain lncRNAs are associated with recurrence, metastasis, and prognosis of cancer. It is also proved that overexpression of certain lncRNAs, behaving like oncogenes, can promote matrix invasion of cancer cells and tumor growth. In this review, we focus our attention on lncRNAs those have been validated in human cancer tissues to suggest reasonable strategies for future research. We introduce an update view of lncRNA, extract cancer-related lncRNAs from literature, and describe the known functions and possible underlying molecular mechanisms of some well investigated lncRNAs (MALAT1, HOX antisense intergenic RNA, and highly upregulated in hepatocellular cancer), as well as their current and potential future application in cancer diagnosis (PCA3) and treatment (H19).

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1Somatic copy-number variations (CNV) may drive cancer progression through both coding and 2 noncoding transcripts. However, noncoding transcripts resulting from CNV are largely unknown, 3 especially for circular RNAs. By integrating bioinformatics analyses of alerted circRNAs and 4 focal CNV in lung adenocarcinoma (LAC), we identify a proto-oncogenic circular RNA 5 (circPRKCI) from the 3q26.2 amplicon, one of the most frequent genomic aberrations in multiple 6 cancers. circPRKCI was overexpressed in LAC tissues, in part due to amplification of the 3q26.2 7 locus, and promoted proliferation and tumorigenesis of LAC. circPRKCI functioned as a sponge 8 for both miR-545 and miR-589 and abrogated their suppression of the pro-tumorigenic 9 transcription factor E2F7. Intra-tumor injection of cholesterol-conjugated siRNA specifically 10 targeting circPRKCI inhibited tumor growth in a patient-derived LAC xenograft model. In 11 summary, circPRKCI is crucial for tumorigenesis and may serve as a potential therapeutic target in 12 LAC patients. 13

Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent and deadly types of cancer worldwide especially in Eastern Asia and the prognosis of ESCC remain poor. Recent evidence suggests that circular RNAs (circRNAs) play important roles in multiple diseases, including cancer. In this study, we characterized a novel circRNA termed hsa_circ_0067934 in ESCC tumor tissues and cell lines. We analyzed a cohort of 51 patients and found that hsa_circ_0067934 was significantly overexpressed in ESCC tissues compared with paired adjacent normal tissues. The high expression level of hsa_circ_0067934 was associated with poor differentiation (P = 0.025), I-II T stage (P = 0.04), and I-II TNM stage (P = 0.021). The in vitro silence of hsa_circ_0067934 by siRNA inhibited the proliferation and migration of ESCC cells and blocked cell cycle progression. Cell fraction analyses and fluorescence in situ hybridization detected that hsa_circ_0067934 was mostly located in the cytoplasm. Our findings suggest that hsa_circ_0067934 is upregulated in ESCC tumor tissue. Our data suggest that hsa_circ_0067934 represents a novel potential biomarker and therapeutic target of ESCC.

Cancer-testis (CT) genes represent the similarity between the processes of spermatogenesis and tumorigenesis. It is possible that their selective expression pattern can help identify driver genes in cancer. In this study, we integrate transcriptomics data from multiple databases and systematically identify 876 new CT genes in 19 cancer types. We explore their relationship with testis-specific regulatory elements. We propose that extremely highly expressed CT genes (EECTGs) are potential drivers activated through epigenetic mechanisms. We find mutually exclusive associations between EECTGs and somatic mutations in mutated genes, such as PIK3CA in breast cancer. We also provide evidence that promoter demethylation and close non-coding RNAs (namely, CT-ncRNAs) may be two mechanisms to reactivate EECTG gene expression. We show that the meiosis-related EECTG (MEIOB) and its nearby CT-ncRNA have a role in tumorigenesis in lung adenocarcinoma. Our findings provide methods for identifying epigenetic-driver genes of cancer, which could serve as targets of future cancer therapies.

PURPOSE ADJUVANT-CTONG1104 (ClinicalTrials.gov identifier: NCT01405079 ), a randomized phase III trial, showed that adjuvant gefitinib treatment significantly improved disease-free survival (DFS) versus vinorelbine plus cisplatin (VP) in patients with epidermal growth factor receptor ( EGFR) mutation-positive resected stage II-IIIA (N1-N2) non–small-cell lung cancer (NSCLC). Here, we report the final overall survival (OS) results. METHODS From September 2011 to April 2014, 222 patients from 27 sites were randomly assigned 1:1 to adjuvant gefitinib (n = 111) or VP (n = 111). Patients with resected stage II-IIIA (N1-N2) NSCLC and EGFR-activating mutation were enrolled, receiving gefitinib for 24 months or VP every 3 weeks for four cycles. The primary end point was DFS (intention-to-treat [ITT] population). Secondary end points included OS, 3-, 5-year (y) DFS rates, and 5-year OS rate. Post hoc analysis was conducted for subsequent therapy data. RESULTS Median follow-up was 80.0 months. Median OS (ITT) was 75.5 and 62.8 months with gefitinib and VP, respectively (hazard ratio [HR], 0.92; 95% CI, 0.62 to 1.36; P = .674); respective 5-year OS rates were 53.2% and 51.2% ( P = .784). Subsequent therapy was administered upon progression in 68.4% and 73.6% of patients receiving gefitinib and VP, respectively. Subsequent targeted therapy contributed most to OS (HR, 0.23; 95% CI, 0.14 to 0.38) compared with no subsequent therapy. Updated 3y DFS rates were 39.6% and 32. 5% with gefitinib and VP ( P = .316) and 5y DFS rates were 22. 6% and 23.2% ( P = .928), respectively. CONCLUSION Adjuvant therapy with gefitinib in patients with early-stage NSCLC and EGFR mutation demonstrated improved DFS over standard of care chemotherapy. Although this DFS advantage did not translate to a significant OS difference, OS with adjuvant gefitinib was one of the longest observed in this patient group compared with historic data.