In cancer biology,mesenchymal stem cells(MSCs)display aspects that can appear contradictory.On one hand,these cells possess several features which give them the ability to specifically target and then sustain cancer c...In cancer biology,mesenchymal stem cells(MSCs)display aspects that can appear contradictory.On one hand,these cells possess several features which give them the ability to specifically target and then sustain cancer cells in their ability to survive the multifaceted host response against cancer.On the other hand,due to this excellent aptitude to home-in on tumor tissues,regardless their location in the host’s body,MSCs are considered to be extremely selective vehicles to reach cancer cells specifically.Recently,MSC sustainment of cancer cell growth is a hot research topic.Indeed,these cells are known to sustain tumor angiogenesis and metastasis formation,to create a microenvironment favorable for cancer cell growth and to down-modulate the immune system capabilities in the host organism.On the other hand,since scientists became able to take advantage of their extremely selective capability to target cancer cells,MSCs are now also thought of in a different light.Indeed,MSCs are now considered a promising vehicle for local expression or delivery of even particularly toxic anticancer agents,ranging from Herpes Simplex Virus to locally-acting antineoplastic drugs.On this basis,investigation is now focused on how to impair the pro-neoplastic features of MSCs on one hand whilst taking advantage of their specific tropism toward cancer cells,on the other.As with the two faces of Janus,this review will concisely explore the research activity in these two apparently conflicting fields.展开更多
During development of the peripheral nervous system (PNS), Schwann cells (SCs) wrap individual axons to form myelin sheaths, which act as surrounding insulators and markedly enhance the propagation of the action poten...During development of the peripheral nervous system (PNS), Schwann cells (SCs) wrap individual axons to form myelin sheaths, which act as surrounding insulators and markedly enhance the propagation of the action potential. In peripheral neuropathies such as Guillain-Barré syndrome (GBS) and inherited demyelinating Charcot-Marie-Tooth (CMT) disease and diabetic neuropathies, chronic demyelination and defective remyelination are repeated, causing more severe neuropathies. It is thus thought that development of a drug that promotes proper myelination with minimal side effects could provide an effective therapy for these diseases. As yet, however, little is known about therapeutic target molecules and genetically-modified mice for testing such approaches. We previously cloned the dock7 gene and characterized Dock7 as the regulator controlling SC myelination;however, an important issue, whether knockdown of Dock7 specifically affects myelination by SCs but not leaves neurons unaffected, has remained unclear. Here, we generate newly-produced transgenic mice harboring short-hairpin RNA (shRNA) targeting Dock7. We also describe that Dock7 shRNA transgenic mice exhibit enhanced myelin thickness without affecting axon thickness in sciatic nerves of the PNS, as reduced thickness of the axon diameter is the primary indicator of denatured neurons. Similarly, purified in vitro SC-neuronal cocultures established from transgenic mice exhibit enhanced formation of myelin segments, suggesting that knockdown of Dock7 promotes myelination by SCs. Collectively, Dock7 knockdown specifically affects SC myelination in sciatic nerves, providing evidence that Dock7 may be a promising drug-target-specific molecules for developing a therapy for peripheral neuropathies that aims to enhance myeliantion.展开更多
基金Supported by Grants from Associazione Italiana Ricerca sul Cancro(AIRC) to Paggi MGMinistero della Salute grants to Paggi MGfrom Sbarro Health Research Organization funds to Galderisi U and Giordano A
文摘In cancer biology,mesenchymal stem cells(MSCs)display aspects that can appear contradictory.On one hand,these cells possess several features which give them the ability to specifically target and then sustain cancer cells in their ability to survive the multifaceted host response against cancer.On the other hand,due to this excellent aptitude to home-in on tumor tissues,regardless their location in the host’s body,MSCs are considered to be extremely selective vehicles to reach cancer cells specifically.Recently,MSC sustainment of cancer cell growth is a hot research topic.Indeed,these cells are known to sustain tumor angiogenesis and metastasis formation,to create a microenvironment favorable for cancer cell growth and to down-modulate the immune system capabilities in the host organism.On the other hand,since scientists became able to take advantage of their extremely selective capability to target cancer cells,MSCs are now also thought of in a different light.Indeed,MSCs are now considered a promising vehicle for local expression or delivery of even particularly toxic anticancer agents,ranging from Herpes Simplex Virus to locally-acting antineoplastic drugs.On this basis,investigation is now focused on how to impair the pro-neoplastic features of MSCs on one hand whilst taking advantage of their specific tropism toward cancer cells,on the other.As with the two faces of Janus,this review will concisely explore the research activity in these two apparently conflicting fields.
文摘During development of the peripheral nervous system (PNS), Schwann cells (SCs) wrap individual axons to form myelin sheaths, which act as surrounding insulators and markedly enhance the propagation of the action potential. In peripheral neuropathies such as Guillain-Barré syndrome (GBS) and inherited demyelinating Charcot-Marie-Tooth (CMT) disease and diabetic neuropathies, chronic demyelination and defective remyelination are repeated, causing more severe neuropathies. It is thus thought that development of a drug that promotes proper myelination with minimal side effects could provide an effective therapy for these diseases. As yet, however, little is known about therapeutic target molecules and genetically-modified mice for testing such approaches. We previously cloned the dock7 gene and characterized Dock7 as the regulator controlling SC myelination;however, an important issue, whether knockdown of Dock7 specifically affects myelination by SCs but not leaves neurons unaffected, has remained unclear. Here, we generate newly-produced transgenic mice harboring short-hairpin RNA (shRNA) targeting Dock7. We also describe that Dock7 shRNA transgenic mice exhibit enhanced myelin thickness without affecting axon thickness in sciatic nerves of the PNS, as reduced thickness of the axon diameter is the primary indicator of denatured neurons. Similarly, purified in vitro SC-neuronal cocultures established from transgenic mice exhibit enhanced formation of myelin segments, suggesting that knockdown of Dock7 promotes myelination by SCs. Collectively, Dock7 knockdown specifically affects SC myelination in sciatic nerves, providing evidence that Dock7 may be a promising drug-target-specific molecules for developing a therapy for peripheral neuropathies that aims to enhance myeliantion.
