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Glioblastomas are highly heterogeneous brain tumors. Despite the availability of standard treatment for glioblastoma multiforme (GBM), i.e., Stupp protocol, which involves surgical resection followed by radiotherapy and chemotherapy, glioblastoma remains refractory to treatment and recurrence is inevitable. Moreover, the biology of recurrent glioblastoma remains unclear. Increasing evidence has shown that intratumoral heterogeneity and the tumor microenvironment contribute to therapeutic resistance. However, the interaction between intracellular heterogeneity and drug resistance in recurrent GBMs remains controversial. The aim of this study was to map the transcriptome landscape of cancer cells and the tumor heterogeneity and tumor microenvironment in recurrent and drug‐resistant GBMs at a single‐cell resolution and further explore the mechanism of drug resistance of GBMs. We analyzed six tumor tissue samples from three patients with primary GBM and three patients with recurrent GBM in which recurrence and drug resistance developed after treatment with the standard Stupp protocol using single‐cell RNA sequencing. Using unbiased clustering, nine major cell clusters were identified. Upregulation of the expression of stemness‐related and cell‐cycle‐related genes was observed in recurrent GBM cells. Compared with the initial GBM tissues, recurrent GBM tissues showed a decreased proportion of microglia, consistent with previous reports. Finally, vascular endothelial growth factor A expression and the blood–brain barrier permeability were high, and the O6‐methylguanine DNA methyltransferase‐related signaling pathway was activated in recurrent GBM. Our results delineate the single‐cell map of recurrent glioblastoma, tumor heterogeneity, tumor microenvironment, and drug‐resistance mechanisms, providing new insights into treatment strategies for recurrent glioblastomas. [ABSTRACT FROM AUTHOR]

Although pancreatic cancer often invades peripancreatic adipose tissue, little information is known about cancer‐adipocyte interaction. We first investigated the ability of adipocytes to de‐differentiate to cancer‐associated adipocytes (CAAs) by co‐culturing with pancreatic cancer cells. We then examined the effects of CAA‐conditioned medium (CAA‐CM) on the malignant characteristics of cancer cells, the mechanism underlying those effects, and their clinical relevance in pancreatic cancer. When 3T3‐L1 adipocytes were co‐cultured with pancreatic cancer cells (PANC‐1) using the Transwell system, adipocytes lost their lipid droplets and changed morphologically to fibroblast‐like cells (CAA). Adipocyte‐specific marker mRNA levels significantly decreased but those of fibroblast‐specific markers appeared, characteristic findings of CAA, as revealed by real‐time PCR. When PANC‐1 cells were cultured with CAA‐CM, significantly higher migration/invasion capability, chemoresistance, and epithelial‐mesenchymal transition (EMT) properties were observed compared with control cells. To investigate the mechanism underlying these effects, we performed microarray analysis of PANC‐1 cells cultured with CAA‐CM and found a 78.5‐fold higher expression of SAA1 compared with control cells. When the SAA1 gene in PANC‐1 cells was knocked down with SAA1 siRNA, migration/invasion capability, chemoresistance, and EMT properties were significantly attenuated compared with control cells. Immunohistochemical analysis on human pancreatic cancer tissues revealed positive SAA1 expression in 46/61 (75.4%). Overall survival in the SAA1‐positive group was significantly shorter than in the SAA1‐negative group (P =.013). In conclusion, we demonstrated that pancreatic cancer cells induced de‐differentiation in adipocytes toward CAA, and that CAA promoted malignant characteristics of pancreatic cancer via SAA1 expression, suggesting that SAA1 is a novel therapeutic target in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Milk fat globule‐epidermal growth factor factor 8 (MFG‐E8) is secreted from macrophages and is known to induce immunological tolerance mediated by regulatory T cells. However, the roles of the MFG‐E8 that is expressed by cancer cells have not yet been fully examined. Expression of MFG‐E8 was examined using immunohistochemistry in surgical samples from 134 patients with esophageal squamous cell carcinoma. The relationships between MFG‐E8 expression levels and clinicopathological factors, including tumor‐infiltrating lymphocytes, were evaluated. High MFG‐E8 expression was observed in 23.9% of the patients. The patients with tumors highly expressing MFG‐E8 had a significantly higher percentage of neoadjuvant chemotherapy (NAC) history (P < .0001) and shorter relapse‐free survival (P = 0.012) and overall survival (OS; P = .0047). On subgroup analysis, according to NAC history, patients with high MFG‐E8 expression had significantly shorter relapse‐free survival (P = .027) and OS (P = .0039) only when they had been treated with NAC. Furthermore, tumors with high MFG‐E8 expression had a significantly lower ratio of CD8+ T cells/regulatory T cells in tumor‐infiltrating lymphocytes (P = .042) only in the patients treated with NAC, and those with a lower ratio had a shorter OS (P = .026). High MFG‐E8 expression was also found to be an independent prognostic factor in multivariate analysis. The abundant MFG‐E8 expression in esophageal squamous cell carcinoma might have a negative influence on the long‐term survival of patients after chemotherapy by affecting T‐cell regulation in the tumor microenvironment. Esophageal cancer patients with high MFG‐E8 expression had worse overall survival and relapse‐free survival in the subgroup with preoperative chemotherapy. The abundant MFG‐E8 expression in esophageal squamous cell carcinoma might have a negative influence on the long‐term survival of patients after chemotherapy by affecting T‐cell regulation in the tumor microenvironment. [ABSTRACT FROM AUTHOR]

The composition of genetic material in extracellular vesicles (EV) has sparked interest particularly in the potential for horizontal gene transfer by EV. Although the RNA content of EV has been studied extensively, few reports have examined the DNA content of EV. It is still unclear how DNA is packaged inside EV, and whether they are functional in recipient cells. In this review, we describe the biological significance of genetic material in EV and their possible impacts in recipient cells, with focus on DNA from cancer cell-derived EV and the potential roles they may play in the cancer microenvironment. Another important feature of the genetic content of EV is the presence of retrotransposon elements. In this review, we discuss the possibility of an EV-mediated mechanism for the dispersal of retrotransposon elements, and their potential involvement in the development of genetically influenced diseases. In addition to this, we discuss the potential involvement of EV in the transfer of genetic material across species, and their possible impacts in modulating genome evolution. [ABSTRACT FROM AUTHOR]

Metastasis and growth in neoplastic lesions requires the multistep regulation of microenvironmental factors. We aimed to elucidate the microenvironmental changes in the process of lymphatic metastasis of lung squamous cell carcinoma. We examined the morphological characteristics of 102 cases of primary tumor ( PT), 50 of intralymphatic tumor ( ILT), 51 of lymph node ( LN) micrometastasis ( LN-Mic; ≤2 mm in size), and 82 of LN macrometastasis ( LN-Mac; ≥10 mm in size). Afterwards we evaluated the expression of nine molecules (epidermal growth factor receptor, fibroblast growth factor receptor 2, CD44, aldehyde dehydrogenase 1, Podoplanin, E-cadherin, S100A4, geminin, and ezrin) in matched PT, ILT, LN-Mic, and LN-Mac from 23 of these cases. The number of smooth muscle actin α-positive fibroblasts, CD34-positive microvessels and CD204-positive macrophages were also examined. As a result, the mitotic index of tumor cells was significantly lower in ILT and LN-Mic than PT and LN-Mac ( P < 0.001). Moreover, stromal reaction in ILT and LN-Mic was less prominent than in PT and LN-Mac ( P < 0.001). Immunohistochemical study revealed that epidermal growth factor receptor expression level and frequency of geminin-positive cells in ILT and LN-Mic were significantly lower than in PT and LN-Mac ( P < 0.05). The number of stromal cells indicated by staining of CD34, CD204, and smooth muscle actin α in ILT and LN-Mic was also significantly lower than in PT and LN-Mac ( P < 0.05). In lung squamous cell carcinoma, drastic microenvironmental changes (e.g., growth factor receptor expression and proliferative capacity of tumor cells and structural changes in stromal cells) occur during both the process of lymphatic permeation and the progression into macrometastases. [ABSTRACT FROM AUTHOR]