TY - JOUR
T1 - In vitro sarcoma cells release a lipophilic substance that activates the pain transduction system via TRPV1
AU - Lautner, Meeghan A.
AU - Ruparel, Shivani B.
AU - Patil, Mayur J.
AU - Hargreaves, Kenneth M.
N1 - Funding Information:
ACKNOWLEDGMENT The authors would like to express sincere gratitude to Paul Chen, Phoebe Scotland, and Jill Fehrenbacher for their assistance with the technical aspects of this manuscript. We would also like to thank Drs. Steven Wolf and John Cornell for their assistance in editing the manuscript. This project was funded in part by NIH NRSA F32CA136300-2 awarded to M.A.L.
PY - 2011/3
Y1 - 2011/3
N2 - Background. Despite success in treating many forms of cancer, pain associated with malignancy remains a serious clinical issue with a poorly understood etiology. This study determined if certain sarcoma cell lines produced a soluble factor that activates the TRPV1 ion channel expressed on nociceptive sensory neurons, thereby activating a major pain transduction system. Materials and Methods. Trigeminal ganglia were harvested from rats and cultured. A rhabdomyosarcoma (CRL1598) and osteosarcoma (CRL 1543) cell line were grown to 75% confluency. Conditioned media (CM) was collected after 24 h of exposure and subjected to reverse phase chromatography. Neuronal activation in the presence of CM was measured using iCGRP RIA and calcium imaging after treatment with vehicle or I-RTX, a potent TRPV1 antagonist. Data were analyzed by ANOVA/Bonferroni or t test. Results. The rhabdomyosarcoma CM produced a 4-fold increase in iCGRP release compared with control media (P<0..001). The osteosarcoma cell line CM produced a 7-fold increase in iCGRP release compared with control media (P<0..001). This evoked iCGRP release was via TRPV1 activation since the effect was blocked by the antagonist I-RTX. The application of rhabdomyosarcomaCM produced about a 4-fold increase in [Ca2+]I levels (P<0..001), and this effect was blocked by pretreatment with the TRPV1 antagonist, I-RTX. Conclusions. We have shown that certain sarcoma cell lines produce a soluble, lipophilic factor that activates the peripheral nociceptor transduction system via TRPV1 activation, thereby contributing to cancer pain. Further investigations are needed to develop tumor-specific analgesics that do not produce unwanted or harmful sideeffects.
AB - Background. Despite success in treating many forms of cancer, pain associated with malignancy remains a serious clinical issue with a poorly understood etiology. This study determined if certain sarcoma cell lines produced a soluble factor that activates the TRPV1 ion channel expressed on nociceptive sensory neurons, thereby activating a major pain transduction system. Materials and Methods. Trigeminal ganglia were harvested from rats and cultured. A rhabdomyosarcoma (CRL1598) and osteosarcoma (CRL 1543) cell line were grown to 75% confluency. Conditioned media (CM) was collected after 24 h of exposure and subjected to reverse phase chromatography. Neuronal activation in the presence of CM was measured using iCGRP RIA and calcium imaging after treatment with vehicle or I-RTX, a potent TRPV1 antagonist. Data were analyzed by ANOVA/Bonferroni or t test. Results. The rhabdomyosarcoma CM produced a 4-fold increase in iCGRP release compared with control media (P<0..001). The osteosarcoma cell line CM produced a 7-fold increase in iCGRP release compared with control media (P<0..001). This evoked iCGRP release was via TRPV1 activation since the effect was blocked by the antagonist I-RTX. The application of rhabdomyosarcomaCM produced about a 4-fold increase in [Ca2+]I levels (P<0..001), and this effect was blocked by pretreatment with the TRPV1 antagonist, I-RTX. Conclusions. We have shown that certain sarcoma cell lines produce a soluble, lipophilic factor that activates the peripheral nociceptor transduction system via TRPV1 activation, thereby contributing to cancer pain. Further investigations are needed to develop tumor-specific analgesics that do not produce unwanted or harmful sideeffects.
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U2 - 10.1245/s10434-010-1328-1
DO - 10.1245/s10434-010-1328-1
M3 - Article
C2 - 20842457
AN - SCOPUS:79955718744
VL - 18
SP - 866
EP - 871
JO - Annals of Surgical Oncology
JF - Annals of Surgical Oncology
SN - 1068-9265
IS - 3
ER -