The significant influence of tumor stroma on malignant cells has been extensively investigated in this era of targeted therapy.The tumor microenvironment,as a dynamic system,is orchestrated by various cells including ...The significant influence of tumor stroma on malignant cells has been extensively investigated in this era of targeted therapy.The tumor microenvironment,as a dynamic system,is orchestrated by various cells including tumor vascular composing cells,inflammatory cells and fibroblasts.As a major and important component in tumor stroma,increasing evidence has shown that spindle-shaped cancer-associated fibroblasts(CAFs)are a significant modifier of cancer evolution,and promote tumorigenesis,tumor invasion and metastasis by stimulating angiogenesis,malignant cell survival,epithelial-mesenchymal transition(EMT)and proliferation via direct cell-to-cell contact or secretion of soluble factors in most digestive solid tumors.CAFs are thought to be activated,characterized bythe expression ofα-smooth muscle actin,fibroblast activated protein,fibroblast specific protein,vimentin,fibronectin,etc.They are hypothesized to originate from normal or aged fibroblasts,bone marrow-derived mesenchymal cells,or vascular endothelial cells.EMT may also be an important process generating CAFs,and most probably,CAFs may originate from multiple cells.A close link exists between EMT,tumor stem cells,and chemo-resistance of tumor cells,which is largely orchestrated by CAFs.CAFs significantly induce immunosuppression,and may be a prognostic marker in various malignancies.Targeted therapy toward CAFs has displayed promising anticancer efficacy,which further reinforces the necessity to explore the relationship between CAFs and their hosts.展开更多
The tumor microenvironment(TME) is complex and constantly evolving. This is due, in part, to the crosstalk between tumor cells and the multiple cell types that comprise the TME, which results in a heterogeneous popula...The tumor microenvironment(TME) is complex and constantly evolving. This is due, in part, to the crosstalk between tumor cells and the multiple cell types that comprise the TME, which results in a heterogeneous population of tumor cells and TME cells. This review will focus on two stromal cell types, the cancerassociated adipocyte(CAA) and the cancer-associated fibroblast(CAF). In the clinic, the presence of CAAs and CAFs in the TME translates to poor prognosis in multiple tumor types. CAAs and CAFs have an activated phenotype and produce growth factors, inflammatory factors, cytokines, chemokines, extracellular matrix components, and proteases in an accelerated and aberrant fashion. Through this activated state, CAAs and CAFs remodel the TME, thereby driving all aspects of tumor progression, including tumor growth and survival, chemoresistance, tumor vascularization, tumor invasion, and tumor cell metastasis. Similarities in the tumorpromoting functions of CAAs and CAFs suggest that a multipronged therapeutic approach may be necessary to achieve maximal impact on disease. While CAAs and CAFs are thought to arise from tissues adjacent to the tumor, multiple alternative origins for CAAs and CAFs have recently been identified. Recent studies from our lab and others suggest that the hematopoietic stem cell, through the myeloid lineage, may serve as a progenitor for CAAs and CAFs. We hypothesize that the multiple origins of CAAs and CAFs may contribute to the heterogeneity seen in the TME. Thus, a better understanding of the origin of CAAs and CAFs, how this origin impacts their functions in the TME, and thetemporal participation of uniquely originating TME cells may lead to novel or improved anti-tumor therapeutics.展开更多
Background: Pancreatic ductal adenocarcinoma(PDAC) is a highly malignant solid tumor with a dismal prognosis. The stroma component makes up to 90% of the tumor mass and is thought to be one of the main reasons for the...Background: Pancreatic ductal adenocarcinoma(PDAC) is a highly malignant solid tumor with a dismal prognosis. The stroma component makes up to 90% of the tumor mass and is thought to be one of the main reasons for the tumor’s high chemoresistance. Cancer associated fibroblasts(CAFs) have previously been identified to be the key stromal players. This is the first time we provide detailed in vitro experiments investigating tumor–stromal interactions when exposed to three well-known chemotherapeutic agents. Methods: Monocultures, indirect and direct co-cultures of two PDAC cell lines(AsPC and Panc-1) and six primary patients derived CAFs were treated with gemcitabine, nab-paclitaxel and the γ-secretaseinhibitor(GSI) DAPT. The cell viability of each component was measured with XTT. Finally, IL-6 concentrations of the supernatants were analyzed. Results: On the contrary to PDAC cell lines, CAF monocultures hardly responded to any treatment which suggested that stroma(CAFs) itself is more resistant to standard chemo-treatments than the epithelial cancer cells. Moreover, only a weak chemotherapeutic response was observed in direct co-cultures of cancer cells with CAFs. A change in the morphology of direct co-cultures was accompanied with the chemoresistance. CAFs were observed to build cage-like structures around agglomerates of tumor cells. High levels of IL-6 were also associated with a reduced response to therapy. Indirect co-cultures make the tumor–stromal interaction more complex. Conclusions: CAFs are highly chemoresistant. Direct cell–cell contact and high levels of IL-6 correlate with a high chemoresistance.展开更多
文摘The significant influence of tumor stroma on malignant cells has been extensively investigated in this era of targeted therapy.The tumor microenvironment,as a dynamic system,is orchestrated by various cells including tumor vascular composing cells,inflammatory cells and fibroblasts.As a major and important component in tumor stroma,increasing evidence has shown that spindle-shaped cancer-associated fibroblasts(CAFs)are a significant modifier of cancer evolution,and promote tumorigenesis,tumor invasion and metastasis by stimulating angiogenesis,malignant cell survival,epithelial-mesenchymal transition(EMT)and proliferation via direct cell-to-cell contact or secretion of soluble factors in most digestive solid tumors.CAFs are thought to be activated,characterized bythe expression ofα-smooth muscle actin,fibroblast activated protein,fibroblast specific protein,vimentin,fibronectin,etc.They are hypothesized to originate from normal or aged fibroblasts,bone marrow-derived mesenchymal cells,or vascular endothelial cells.EMT may also be an important process generating CAFs,and most probably,CAFs may originate from multiple cells.A close link exists between EMT,tumor stem cells,and chemo-resistance of tumor cells,which is largely orchestrated by CAFs.CAFs significantly induce immunosuppression,and may be a prognostic marker in various malignancies.Targeted therapy toward CAFs has displayed promising anticancer efficacy,which further reinforces the necessity to explore the relationship between CAFs and their hosts.
基金Supported by In part by the NIH/NCI(R01 CA148772,ACL)the Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs(Merit Awards,ACL)the Hollings Cancer Center(Translational Research Pilot Project,P30 CA138313,ACL)
文摘The tumor microenvironment(TME) is complex and constantly evolving. This is due, in part, to the crosstalk between tumor cells and the multiple cell types that comprise the TME, which results in a heterogeneous population of tumor cells and TME cells. This review will focus on two stromal cell types, the cancerassociated adipocyte(CAA) and the cancer-associated fibroblast(CAF). In the clinic, the presence of CAAs and CAFs in the TME translates to poor prognosis in multiple tumor types. CAAs and CAFs have an activated phenotype and produce growth factors, inflammatory factors, cytokines, chemokines, extracellular matrix components, and proteases in an accelerated and aberrant fashion. Through this activated state, CAAs and CAFs remodel the TME, thereby driving all aspects of tumor progression, including tumor growth and survival, chemoresistance, tumor vascularization, tumor invasion, and tumor cell metastasis. Similarities in the tumorpromoting functions of CAAs and CAFs suggest that a multipronged therapeutic approach may be necessary to achieve maximal impact on disease. While CAAs and CAFs are thought to arise from tissues adjacent to the tumor, multiple alternative origins for CAAs and CAFs have recently been identified. Recent studies from our lab and others suggest that the hematopoietic stem cell, through the myeloid lineage, may serve as a progenitor for CAAs and CAFs. We hypothesize that the multiple origins of CAAs and CAFs may contribute to the heterogeneity seen in the TME. Thus, a better understanding of the origin of CAAs and CAFs, how this origin impacts their functions in the TME, and thetemporal participation of uniquely originating TME cells may lead to novel or improved anti-tumor therapeutics.
基金supported by a grant from Charité–Universitaetsmedizin Berlin in house funding
文摘Background: Pancreatic ductal adenocarcinoma(PDAC) is a highly malignant solid tumor with a dismal prognosis. The stroma component makes up to 90% of the tumor mass and is thought to be one of the main reasons for the tumor’s high chemoresistance. Cancer associated fibroblasts(CAFs) have previously been identified to be the key stromal players. This is the first time we provide detailed in vitro experiments investigating tumor–stromal interactions when exposed to three well-known chemotherapeutic agents. Methods: Monocultures, indirect and direct co-cultures of two PDAC cell lines(AsPC and Panc-1) and six primary patients derived CAFs were treated with gemcitabine, nab-paclitaxel and the γ-secretaseinhibitor(GSI) DAPT. The cell viability of each component was measured with XTT. Finally, IL-6 concentrations of the supernatants were analyzed. Results: On the contrary to PDAC cell lines, CAF monocultures hardly responded to any treatment which suggested that stroma(CAFs) itself is more resistant to standard chemo-treatments than the epithelial cancer cells. Moreover, only a weak chemotherapeutic response was observed in direct co-cultures of cancer cells with CAFs. A change in the morphology of direct co-cultures was accompanied with the chemoresistance. CAFs were observed to build cage-like structures around agglomerates of tumor cells. High levels of IL-6 were also associated with a reduced response to therapy. Indirect co-cultures make the tumor–stromal interaction more complex. Conclusions: CAFs are highly chemoresistant. Direct cell–cell contact and high levels of IL-6 correlate with a high chemoresistance.
