Senescent cells accumulate in tissues during aging and are considered to underlie several aging-associated phenotypes and diseases. We recently reported that the elimination of p19ARF -expressing senescent cells from lung tissue restored tissue function and gene expression in middle-aged (12-month-old) mice. The aging of lung tissue increases the risk of pulmonary diseases such as emphysema, and cellular senescence is accelerated in emphysema patients. However, there is currently no direct evidence to show that cellular senescence promotes the pathology of emphysema, and the involvement of senescence in the development of this disease has yet to be clarified. We herein demonstrated that p19ARF facilitated the development of pulmonary emphysema in mice. The elimination of p19ARF -expressing cells prevented lung tissue from elastase-induced lung dysfunction. These effects appeared to depend on reduced pulmonary inflammation, which is enhanced after elastase stimulation. Furthermore, the administration of a senolytic drug that selectively kills senescent cells attenuated emphysema-associated pathologies. These results strongly suggest the potential of senescent cells as therapeutic/preventive targets for pulmonary emphysema.

Transforming growth factor β1 (TGFβ1) regulates a variety of cellular functions, including cell growth, apoptosis and differentiation. The aim of the current study was to investigate the alterations of phenotypic events in the long-term exposure of prostate cancer (PCa) cells to TGFβ1 and its effect on macrophage-differentiated cells. The PCa cell line, PC-3, and the subclone, M1, were exposed to TGFβ1 for short- or long-term periods. TGFβ1 signaling was assessed by Smad3 phosphorylation, and non-canonical signaling was analyzed by quantitative polymerase chain reaction-based regulatory gene expression profiles. TGFβ1-exposed PCa cells were also co-cultured with phorbol 12-myristate 13-acetate (PMA)-treated THP-1 macrophages as a model of the tumor microenvironment. The phosphorylation of Smad3 in the PCa cells with long-term exposure was lower than that in the PCa cells with short-term exposure. Interleukin-6 mRNA expression in the PMA-treated THP-1 macrophages was significantly downregulated by co-culture with the PCa cells with long-term exposure. Cyclooxygenase-2 expression in the long-term TGFβ1-exposed PCa cells was lower than that in the control PCa cells, and the production of prostaglandin E2 (PGE2) in the long-term TGFβ1-exposed PCa cells was also significantly lower. The results of the current study demonstrated that the long-term TGFβ1 exposure of PCa cells induces phenotypic changes, including the downregulation of PGE2 production. This indicates that prolonged TGFβ-exposed PCa cells may change the cytokine production of macrophages in the tumor microenvironment.

Liquid-based cytology (LBC) has been widely used since 2000. Next-Generation Sequencing (NGS) analysis of residual specimens in LBC fixative may also be performed for pancreatic cancer in the near future. We examined cell morphology, antigenicity and nucleic acids in pancreatic cancer cells at different fixation times using two types of LBC fixatives.

Homology is a mathematical tool to quantify "the contact degree", which can be expressed in terms of Betti numbers. The Betti numbers used in this study consisted of two numbers, b0 (a zero-dimensional Betti number) and b1 (a one-dimensional Betti number). We developed a chromatin homology profile (CHP) method to quantify the chromatin contact degree based on this mathematical tool. Using the CHP method we analyzed the number of holes (surrounded areas = b1 value) formed by the chromatin contact and calculated the maximum value of b1 (b1MAX), the value of b1 exceeding 5 for the first time or Homology Value (HV), and the chromatin density (b1MAX/ns2). We attempted to detect differences in chromatin patterns and differentiate histological types of lung cancer from respiratory cytology using these three features. The HV of cancer cells was significantly lower than that of non-cancerous cells. Furthermore, b1MAX and b1MAX/ns2 showed significant differences between small cell and non-small cell carcinomas and between adenocarcinomas and squamous cell carcinomas, respectively. We quantitatively analyzed the chromatin patterns using homology and showed that the CHP method may be a useful tool for differentiating histological types of lung cancer in respiratory cytology.

Pancreatic cancer develops dense stromal tissue through the desmoplastic reaction. The aim of the present study was to assess the effects of a fibroblast-rich environment on the malignant potential of pancreatic cancer. Cells from the human pancreatic cancer cell line BxPC-3 were mixed at a ratio of 1:3 (fibroblast-rich) or 1:1 (fibroblast-poor) with cells from the human skin fibroblast line ASF-4-1. In the fibroblast-rich co-culture, tumor budding was observed and BxPC-3 cells were found to be more resistant to gemcitabine than those in the fibroblast-poor co-culture. Immunohistochemistry revealed that the expression of mammalian target of rapamycin was increased at the invasive front of fibroblast-rich co-cultures. In addition, in mouse xenografts of fibroblast-rich co-cultures, tumors were larger and had a higher Ki-67 index compared with that of the fibroblast-poor co-culture xenografts. These results indicate that fibroblast-rich co-cultures may promote the malignant potential of the pancreatic cancer cell line BxPC-3, both in vitro and in vivo.