Milk fat globule epithelial growth factor VIII(MFG-E8) is a novel adhesion protein mainly produced by macrophages and dendritic cells; it is expressed in most of the human tissues and functions to prompt cancer progre...Milk fat globule epithelial growth factor VIII(MFG-E8) is a novel adhesion protein mainly produced by macrophages and dendritic cells; it is expressed in most of the human tissues and functions to prompt cancer progression and survival. MFG-E8 contains a signal sequence for secretion, two epidermal growth factor(EGF)-like domains at the NH2 terminus and two discoidin domains with blood-clotting factor V/factor Ⅷ(C1 and C2) at the COOH terminus. The second EGF domain contains an arginine-glycine-aspartic(RGD) integrin-binding motif that engages α_vβ_5 integrins to facilitate cell adhesion and induce integrinmediated signal transduction. Integrin α_vβ_3 associates with VEGF receptor 2, engagement of integrins can promote angiogenesis, which plays key roles in growth, proliferation, and survival of cancer cells. VEGF stimulates the expression of α_vβ_3 and α_vβ_5 integrins on angiogenic vasculature, thereby potentiating effects of VEGF receptor engagement. Mice expressing a mutant form of α_vβ_3 integrin are unable to undergo tyrosine phosphorylation, confirming the important role that this integrin plays in pathological angiogenesis and providing important mechanistic insights. The C-terminus discoidin-like domains promote binding to membrane phospholipids, functioning close to VEGF like angiogenesis. MFG-E8 is an opsonin for apoptotic cells, and it acts as a bridging protein between apoptotic cells and phagocytes. It also influences cell immunities by altering CD4^+ and/or CD8^+ cells. Antibody or small peptide works with MFG-E8 at different functional sites or interacts with EGF-like domains and/or discoidin-like domains may play an important role in anti-angiogenesis or immune restoration. Altering the structures and/or functions of MFG-E8 and/or its domains is promising for development of novel anti-cancer strategies.展开更多
Crizotinib,a small molecular tyrosine kinase inhibitor,manifests dramatic responses in patients with non-small cell lung cancer with echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase(EML4-ALK...Crizotinib,a small molecular tyrosine kinase inhibitor,manifests dramatic responses in patients with non-small cell lung cancer with echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase(EML4-ALK)rearrangements.ALK gene point mutation is the primary mechanism of acquired crizotinib resistance;however,the intrinsic mechanism is not fully understood.Here,we report a patient with a low mutant allele fraction(MAF)of EML4-ALK rearrangement,who experienced primary resistance to crizotinib treatment.The patient was a 66-year-old Chinese man,who had a history of metastatic lung cancer and was treated with first-and third-generation epidermal growth factor receptor tyrosine kinase inhibitors(EGFR TKIs).After 14 months of osimertinib treatment,his disease progressed,and next-generation sequencing was performed from a liquid biopsy of the patient’s blood.An EML4-ALK rearrangement was found and crizotinib was administered.The patient’s lung lesions continued to progress after one month of crizotinib treatment,and pemetrexed-bevacizumab was initiated.After two cycles of chemotherapy,the metastatic cancers shrunk,and the patient maintained stable disease at his last follow-up.EML4-ALK rearrangements can happen in patients with EGFR-positive NSCLC,after acquired resistance to EGFR TKI treatment.The EGFR T790M and C797G mutations occur in cis is a critical mechanism of resistance to osimertinib therapy.The MAF of EML4-ALK rearrangements in cancer cells might be a predictive factor for crizotinib treatment.展开更多
Skin reaction or dermatological toxicities induced by immunotherapy is common.It usually manifests skin rash or erythema and can be cured by skin lotion or steroid.Nivolumab,a human IgG4 programmed cell death protein ...Skin reaction or dermatological toxicities induced by immunotherapy is common.It usually manifests skin rash or erythema and can be cured by skin lotion or steroid.Nivolumab,a human IgG4 programmed cell death protein 1(PD-1)inhibitor,blocks T cells activation preventing signal and allows the immune system to clear cancer cells.Nivolumab was approved in the second-line therapy in squamous cell lung cancer by FDA,with less than 10%unusual skin reaction,like sensory neuropathy,peeling skin,erythema multiforme,vitiligo,and psoriasis.Radiotherapy could aggravate this skin reaction through inflammatory response and promotion of immunity.The combined treatment of anti-PD-1 and radiotherapy represented a new promising therapeutic approach in many studies,but the risk of side effects may be high.We reported a patient with advanced squamous cell lung cancer who suffered from serious skin immune-related adverse events when he was treated with nivolumab and radiotherapy.The immune overreaction of the treatment of anti-PD-1 treatment and radiotherapy might cause these serious skin adverse events.Our report warranted careful workup to reduce the risk of side effects by combinative therapy with anti-PD-1 and radiotherapy.展开更多
基金Supported by a grant from Medical Technology Research Center for Health Development of China National Health and Family Planning Commission(No.W2012FZ007)
文摘Milk fat globule epithelial growth factor VIII(MFG-E8) is a novel adhesion protein mainly produced by macrophages and dendritic cells; it is expressed in most of the human tissues and functions to prompt cancer progression and survival. MFG-E8 contains a signal sequence for secretion, two epidermal growth factor(EGF)-like domains at the NH2 terminus and two discoidin domains with blood-clotting factor V/factor Ⅷ(C1 and C2) at the COOH terminus. The second EGF domain contains an arginine-glycine-aspartic(RGD) integrin-binding motif that engages α_vβ_5 integrins to facilitate cell adhesion and induce integrinmediated signal transduction. Integrin α_vβ_3 associates with VEGF receptor 2, engagement of integrins can promote angiogenesis, which plays key roles in growth, proliferation, and survival of cancer cells. VEGF stimulates the expression of α_vβ_3 and α_vβ_5 integrins on angiogenic vasculature, thereby potentiating effects of VEGF receptor engagement. Mice expressing a mutant form of α_vβ_3 integrin are unable to undergo tyrosine phosphorylation, confirming the important role that this integrin plays in pathological angiogenesis and providing important mechanistic insights. The C-terminus discoidin-like domains promote binding to membrane phospholipids, functioning close to VEGF like angiogenesis. MFG-E8 is an opsonin for apoptotic cells, and it acts as a bridging protein between apoptotic cells and phagocytes. It also influences cell immunities by altering CD4^+ and/or CD8^+ cells. Antibody or small peptide works with MFG-E8 at different functional sites or interacts with EGF-like domains and/or discoidin-like domains may play an important role in anti-angiogenesis or immune restoration. Altering the structures and/or functions of MFG-E8 and/or its domains is promising for development of novel anti-cancer strategies.
文摘Crizotinib,a small molecular tyrosine kinase inhibitor,manifests dramatic responses in patients with non-small cell lung cancer with echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase(EML4-ALK)rearrangements.ALK gene point mutation is the primary mechanism of acquired crizotinib resistance;however,the intrinsic mechanism is not fully understood.Here,we report a patient with a low mutant allele fraction(MAF)of EML4-ALK rearrangement,who experienced primary resistance to crizotinib treatment.The patient was a 66-year-old Chinese man,who had a history of metastatic lung cancer and was treated with first-and third-generation epidermal growth factor receptor tyrosine kinase inhibitors(EGFR TKIs).After 14 months of osimertinib treatment,his disease progressed,and next-generation sequencing was performed from a liquid biopsy of the patient’s blood.An EML4-ALK rearrangement was found and crizotinib was administered.The patient’s lung lesions continued to progress after one month of crizotinib treatment,and pemetrexed-bevacizumab was initiated.After two cycles of chemotherapy,the metastatic cancers shrunk,and the patient maintained stable disease at his last follow-up.EML4-ALK rearrangements can happen in patients with EGFR-positive NSCLC,after acquired resistance to EGFR TKI treatment.The EGFR T790M and C797G mutations occur in cis is a critical mechanism of resistance to osimertinib therapy.The MAF of EML4-ALK rearrangements in cancer cells might be a predictive factor for crizotinib treatment.
文摘Skin reaction or dermatological toxicities induced by immunotherapy is common.It usually manifests skin rash or erythema and can be cured by skin lotion or steroid.Nivolumab,a human IgG4 programmed cell death protein 1(PD-1)inhibitor,blocks T cells activation preventing signal and allows the immune system to clear cancer cells.Nivolumab was approved in the second-line therapy in squamous cell lung cancer by FDA,with less than 10%unusual skin reaction,like sensory neuropathy,peeling skin,erythema multiforme,vitiligo,and psoriasis.Radiotherapy could aggravate this skin reaction through inflammatory response and promotion of immunity.The combined treatment of anti-PD-1 and radiotherapy represented a new promising therapeutic approach in many studies,but the risk of side effects may be high.We reported a patient with advanced squamous cell lung cancer who suffered from serious skin immune-related adverse events when he was treated with nivolumab and radiotherapy.The immune overreaction of the treatment of anti-PD-1 treatment and radiotherapy might cause these serious skin adverse events.Our report warranted careful workup to reduce the risk of side effects by combinative therapy with anti-PD-1 and radiotherapy.
