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Abstract:Cancer evolves through a multistep process that occurs by the temporal accumulation of genetic mutations mediated by intracellular and extracellular cues. We observe that exosomes isolated from pancreatic cancer cells, but not normal pancreatic cells, can initiate the first step of malignant cell transformation. Injection of exosome-initiated transformed cells into mice results in aggressive 5 tumor growth. Using proteomic profiling and DNA sequencing of exosome-treated and transformed cells, we show that cancer cell exosomes act as a classic initiator by causing random genetic changes in recipient cells. Our studies provide new insight into a function of cancer cell exosomes and how they might specifically contribute to orchestrated local cell transformation. was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/360982 doi: bioRxiv preprint first posted online Jul. 3, 2018; 3 in analyzing their possible contribution to transforming a normal cell into a malignant cell. Since pancreatic cancer is a lethal metastatic disease that lacks efficient curative treatment, we raised the question of whether sEV, secreted by pancreatic cancer cells, participate directly in the process of cellular transformation (15).Malignant transformation of a normal cell occurs in a stepwise fashion. Initial changes 5 induced by environmental exposure, even with relatively low doses or genetic cues, can result in the reprogramming of a normal cell to a less differentiated state that is receptive to additional genetic alterations resulting in uncontrolled growth and ultimately cancer. The classic 2-stage in vitro cell transformation assay is a tiered system for transformation that was created for screening potential carcinogenic factors (16-18). In this system, cells are first treated with a suspected 10 carcinogen, called an initiator, which causes random genetic changes in a pool of normal cells.Subsequently, these initiated cells are exposed to a promoter, which induces further genetic alterations resulting in cell transformation and observed as foci on a cell culture plate (Fig. 1A) (18, 19). This 2-stage assay provides sensitivity in detecting a wider range of initiating agents that may not show obvious transforming activity without a promoter (18). With the recent indications 15 that exosomes are emerging contributors to normal physiology and tumor promotion, we asked a simple question: can exosomes function as an initiator or promoter during the transformation of a normal cell to a cancer cell?To address this question, we utilized the classic cell transformation assay with NIH/3T3 cells using 3-methylcholanthrene (MCA) and tetradecanoyl phorbol acetate (TPA) as controls for 20 an initiator and promoter, respectively (Fig. 1A) (18, 20). Untreated cells or cells treated with MCA or TPA alone showed low levels of background foci, as defined by criteria on focus scoring (Fig. 1B and C, ...
Abstract:Cancer evolves through a multistep process that occurs by the temporal accumulation of genetic mutations mediated by intracellular and extracellular cues. We observe that exosomes isolated from pancreatic cancer cells, but not normal pancreatic cells, can initiate the first step of malignant cell transformation. Injection of exosome-initiated transformed cells into mice results in aggressive 5 tumor growth. Using proteomic profiling and DNA sequencing of exosome-treated and transformed cells, we show that cancer cell exosomes act as a classic initiator by causing random genetic changes in recipient cells. Our studies provide new insight into a function of cancer cell exosomes and how they might specifically contribute to orchestrated local cell transformation. was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/360982 doi: bioRxiv preprint first posted online Jul. 3, 2018; 3 in analyzing their possible contribution to transforming a normal cell into a malignant cell. Since pancreatic cancer is a lethal metastatic disease that lacks efficient curative treatment, we raised the question of whether sEV, secreted by pancreatic cancer cells, participate directly in the process of cellular transformation (15).Malignant transformation of a normal cell occurs in a stepwise fashion. Initial changes 5 induced by environmental exposure, even with relatively low doses or genetic cues, can result in the reprogramming of a normal cell to a less differentiated state that is receptive to additional genetic alterations resulting in uncontrolled growth and ultimately cancer. The classic 2-stage in vitro cell transformation assay is a tiered system for transformation that was created for screening potential carcinogenic factors (16-18). In this system, cells are first treated with a suspected 10 carcinogen, called an initiator, which causes random genetic changes in a pool of normal cells.Subsequently, these initiated cells are exposed to a promoter, which induces further genetic alterations resulting in cell transformation and observed as foci on a cell culture plate (Fig. 1A) (18, 19). This 2-stage assay provides sensitivity in detecting a wider range of initiating agents that may not show obvious transforming activity without a promoter (18). With the recent indications 15 that exosomes are emerging contributors to normal physiology and tumor promotion, we asked a simple question: can exosomes function as an initiator or promoter during the transformation of a normal cell to a cancer cell?To address this question, we utilized the classic cell transformation assay with NIH/3T3 cells using 3-methylcholanthrene (MCA) and tetradecanoyl phorbol acetate (TPA) as controls for 20 an initiator and promoter, respectively (Fig. 1A) (18, 20). Untreated cells or cells treated with MCA or TPA alone showed low levels of background foci, as defined by criteria on focus scoring (Fig. 1B and C, ...
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