Ras gene mutation has been observed in more than 30%of cancers,and 90%of pancreatic,lung and colon cancers.Ras proteins(K-Ras,H-Ras,N-Ras)act as molecular switches which are activated by binding to GTP.They play a rol...Ras gene mutation has been observed in more than 30%of cancers,and 90%of pancreatic,lung and colon cancers.Ras proteins(K-Ras,H-Ras,N-Ras)act as molecular switches which are activated by binding to GTP.They play a role in the cascade of cell process control(proliferation and cell division).In the inactive state,transforming GTP to GDP leads to the activation of GTpase in Ras gene.However,the mutation in Ras leads to the loss of internal GTPase activity and permanent activation of the protein.The activated Ras can promote the cell death or stop cell growth,which are facilitated by Ras-association domain family.Various studies have been conducted to determine the importance of losing RASSF proteins in Rasinduced tumors.This paper examines the role of Ras and RASSF proteins.In general,RASSF proteins can be used as a suitable means for targeting a large group of Ras-induced tumors.展开更多
Hippo Tumor Suppressor Pathway is the main pathway for cell growth that regulates tissue enlargement and organ size by limiting cell growth.This pathway is activated in response to cell cycle arrest signals(cell polar...Hippo Tumor Suppressor Pathway is the main pathway for cell growth that regulates tissue enlargement and organ size by limiting cell growth.This pathway is activated in response to cell cycle arrest signals(cell polarity,transduction,and DNA damage)and limited by growth factors or mitogens associated with EGF and LPA.The major pathway consists of the central kinase of Ste20 MAPK(Saccharomyces cerevisiae),Hpo(Drosophila melanogaster)or MST kinases(mammalian)that activates the mammalian AGC kinase dmWts or LATS effector(MST and LATS).YAP in the nucleus work as a cofactor for a wide range of transcription factors involved in proliferation(TEA domain family,TEAD1-4),stem cells(Oct4 mononuclear factor and SMAD-related TGFb effector),differentiation(RUNX1),and Cell cycle/apoptosis control(p53,p63,and p73 family members).This is due to the diverse roles of YAP and may limit tumor progression and establishment.TEAD also coordinates various signal transduction pathways such as Hippo,WNT,TGFb and EGFR,and effects on lack of regulation of TEAD cancerous genes,such as KRAS,BRAF,LKB1,NF2 and MYC,which play essential roles in tumor progression,metastasis,cancer metabolism,immunity,and drug resistance.However,RAS signaling is a pivotal factor in the inactivation of Hippo,which controls EGFR-RAS-RAF-MEK-ERKmediated interaction of Hippo signaling.Thus,the loss of the Hippo pathway may have significant consequences on the targets of RAS-RAF mutations in cancer.展开更多
New approaches to cancer immunotherapy have been developed, showing the ability to harness the immune system to treat and eliminate cancer. For many solid tumors, therapy with checkpoint inhibitors has shown promise. ...New approaches to cancer immunotherapy have been developed, showing the ability to harness the immune system to treat and eliminate cancer. For many solid tumors, therapy with checkpoint inhibitors has shown promise. For hematologic malignancies, adoptive and engineered cell therapies are being widely developed, using cells such as T lymphocytes, as well as natural killer(NK) cells, dendritic cells, and potentially others. Among these adoptive cell therapies, the most active and advanced therapy involves chimeric antigen receptor(CAR)-T cells, which are T cells in which a chimeric antigen receptor is used to redirect specificity and allow T cell recognition, activation and killing of cancers, such as leukemia and lymphoma. Two autologous CAR-T products have been approved by several health authorities,starting with the U.S. Food and Drug Administration(FDA) in 2017. These products have shown powerful, inducing, long-lasting effects against B cell cancers in many cases. In distinction to the results seen in hematologic malignancies, the field of using CAR-T products against solid tumors is in its infancy. Targeting solid tumors and trafficking CAR-T cells into an immunosuppressive microenvironment are both significant challenges. The goal of this review is to summarize some of the most recent aspects of CAR-T cell design and manufacturing that have led to successes in hematological malignancies, allowing the reader to appreciate the barriers that must be overcome to extend CAR-T therapies to solid tumors successfully.展开更多
Cancer stem cells(CSCs)with their self-renewal ability are accepted as cells which initiate tumors.CSCs are regarded as interesting targets for novel anticancer therapeutic agents because of their association with tum...Cancer stem cells(CSCs)with their self-renewal ability are accepted as cells which initiate tumors.CSCs are regarded as interesting targets for novel anticancer therapeutic agents because of their association with tumor recurrence and resistance to conventional therapies,including radiotherapy and chemotherapy.Chimeric antigen receptor(CAR)-T cells are engineered T cells which express an artificial receptor specific for tumor associated antigens(TAAs)by which they accurately target and kill cancer cells.In recent years,CAR-T cell therapy has shown more efficiency in cancer treatment,particularly regarding blood cancers.The expression of specific markers such as TAAs on CSCs in varied cancer types makes them as potent tools for CAR-T cell therapy.Here we review the CSC markers that have been previously targeted with CAR-T cells,as well as the CSC markers that may be used as possible targets for CAR-T cell therapy in the future.Furthermore,we will detail the most important obstacles against CART cell therapy and suggest solutions.展开更多
文摘Ras gene mutation has been observed in more than 30%of cancers,and 90%of pancreatic,lung and colon cancers.Ras proteins(K-Ras,H-Ras,N-Ras)act as molecular switches which are activated by binding to GTP.They play a role in the cascade of cell process control(proliferation and cell division).In the inactive state,transforming GTP to GDP leads to the activation of GTpase in Ras gene.However,the mutation in Ras leads to the loss of internal GTPase activity and permanent activation of the protein.The activated Ras can promote the cell death or stop cell growth,which are facilitated by Ras-association domain family.Various studies have been conducted to determine the importance of losing RASSF proteins in Rasinduced tumors.This paper examines the role of Ras and RASSF proteins.In general,RASSF proteins can be used as a suitable means for targeting a large group of Ras-induced tumors.
文摘Hippo Tumor Suppressor Pathway is the main pathway for cell growth that regulates tissue enlargement and organ size by limiting cell growth.This pathway is activated in response to cell cycle arrest signals(cell polarity,transduction,and DNA damage)and limited by growth factors or mitogens associated with EGF and LPA.The major pathway consists of the central kinase of Ste20 MAPK(Saccharomyces cerevisiae),Hpo(Drosophila melanogaster)or MST kinases(mammalian)that activates the mammalian AGC kinase dmWts or LATS effector(MST and LATS).YAP in the nucleus work as a cofactor for a wide range of transcription factors involved in proliferation(TEA domain family,TEAD1-4),stem cells(Oct4 mononuclear factor and SMAD-related TGFb effector),differentiation(RUNX1),and Cell cycle/apoptosis control(p53,p63,and p73 family members).This is due to the diverse roles of YAP and may limit tumor progression and establishment.TEAD also coordinates various signal transduction pathways such as Hippo,WNT,TGFb and EGFR,and effects on lack of regulation of TEAD cancerous genes,such as KRAS,BRAF,LKB1,NF2 and MYC,which play essential roles in tumor progression,metastasis,cancer metabolism,immunity,and drug resistance.However,RAS signaling is a pivotal factor in the inactivation of Hippo,which controls EGFR-RAS-RAF-MEK-ERKmediated interaction of Hippo signaling.Thus,the loss of the Hippo pathway may have significant consequences on the targets of RAS-RAF mutations in cancer.
文摘New approaches to cancer immunotherapy have been developed, showing the ability to harness the immune system to treat and eliminate cancer. For many solid tumors, therapy with checkpoint inhibitors has shown promise. For hematologic malignancies, adoptive and engineered cell therapies are being widely developed, using cells such as T lymphocytes, as well as natural killer(NK) cells, dendritic cells, and potentially others. Among these adoptive cell therapies, the most active and advanced therapy involves chimeric antigen receptor(CAR)-T cells, which are T cells in which a chimeric antigen receptor is used to redirect specificity and allow T cell recognition, activation and killing of cancers, such as leukemia and lymphoma. Two autologous CAR-T products have been approved by several health authorities,starting with the U.S. Food and Drug Administration(FDA) in 2017. These products have shown powerful, inducing, long-lasting effects against B cell cancers in many cases. In distinction to the results seen in hematologic malignancies, the field of using CAR-T products against solid tumors is in its infancy. Targeting solid tumors and trafficking CAR-T cells into an immunosuppressive microenvironment are both significant challenges. The goal of this review is to summarize some of the most recent aspects of CAR-T cell design and manufacturing that have led to successes in hematological malignancies, allowing the reader to appreciate the barriers that must be overcome to extend CAR-T therapies to solid tumors successfully.
基金supported by Dr.Kazemi Ashtiani Award of Iran’s National Elites Foundation(INEF,Iran)awarded to Hamid Reza Mirzaei
文摘Cancer stem cells(CSCs)with their self-renewal ability are accepted as cells which initiate tumors.CSCs are regarded as interesting targets for novel anticancer therapeutic agents because of their association with tumor recurrence and resistance to conventional therapies,including radiotherapy and chemotherapy.Chimeric antigen receptor(CAR)-T cells are engineered T cells which express an artificial receptor specific for tumor associated antigens(TAAs)by which they accurately target and kill cancer cells.In recent years,CAR-T cell therapy has shown more efficiency in cancer treatment,particularly regarding blood cancers.The expression of specific markers such as TAAs on CSCs in varied cancer types makes them as potent tools for CAR-T cell therapy.Here we review the CSC markers that have been previously targeted with CAR-T cells,as well as the CSC markers that may be used as possible targets for CAR-T cell therapy in the future.Furthermore,we will detail the most important obstacles against CART cell therapy and suggest solutions.
