Latent Neu­ropa­thy in Col­orec­tal Can­cer: Impli­ca­tions for Can­cer Survivorship

Cait­lyn M. Gaffney, Angela M. Casar­il, Iqbal Mah­mud, Bo Wei, Yanyan Jiang, Nathan T. Fiore, Marc A. Pina, Karen M. Valadez, Eliz­a­beth A. Kolb, Fish­er R. Cher­ry, Lei Shi, Ken­neth Dun­ner Jr., Philip L. Loren­zi, Steven R. Reiken, Peter M. Grace, Rajasekaran Mahalingam, There­sa A. Guise, Car­olyn L. Hodo, Andrew J. Shepherd

Col­orec­tal can­cer sur­vivors are at increased risk of devel­op­ing neu­ro­log­i­cal issues, par­tic­u­lar­ly periph­er­al neu­ropa­thy and chron­ic pain. Although pre-exist­ing neu­ropa­thy is a risk fac­tor for chron­ic pain, tumor-induced neu­ropa­thy has not been firm­ly estab­lished in pre-clin­i­cal mod­els. Con­sis­tent with clin­i­cal obser­va­tions, we show that mice with col­orec­tal can­cer devel­op periph­er­al neu­ropa­thy, which was asso­ci­at­ed with sub­tle loco­mo­tor deficits, with­out overt hypersensitivity. 

We detect­ed wide­spread dif­fer­ences in pro-inflam­ma­to­ry cytokines and lipid metabo­lites in periph­er­al nerves from tumor-bear­ing mice. Macrophage accu­mu­la­tion, myelin decom­paction and ryan­odine recep­tor oxi­da­tion were asso­ci­at­ed with dys­func­tion­al cal­ci­um home­osta­sis and reduced spike ampli­tude in sen­so­ry neu­rons. Sim­i­lar alter­ations in plas­ma inflam­ma­to­ry medi­a­tors and lipid metabo­lites were asso­ci­at­ed with neu­ropa­thy and macrophage accu­mu­la­tion in periph­er­al nerves of rhe­sus macaques with col­orec­tal cancer. 

Con­sis­tent­ly, mice with col­orec­tal can­cer exhib­it greater pain sen­si­tiv­i­ty fol­low­ing treat­ment with oxali­platin. These find­ings sug­gest col­orec­tal can­cer is causal­ly linked to a sub­a­cute form of chron­ic inflam­ma­to­ry demyeli­nat­ing polyneu­ropa­thy across species, which may rep­re­sent an under-report­ed, yet impor­tant risk fac­tor for neu­ro­log­i­cal dys­func­tion in col­orec­tal can­cer survivors.

Cait­lyn M. Gaffney, Angela M. Casar­il, Iqbal Mah­mud, Bo Wei, Yanyan Jiang, Nathan T. Fiore, Marc A. Pina, Karen M. Valadez, Eliz­a­beth A. Kolb, Fish­er R. Cher­ry, Lei Shi, Ken­neth Dun­ner Jr., Philip L. Loren­zi, Steven R. Reiken, Peter M. Grace, Rajasekaran Mahalingam, There­sa A. Guise, Car­olyn L. Hodo, Andrew J. Shepherd

Col­orec­tal can­cer sur­vivors are at increased risk of devel­op­ing neu­ro­log­i­cal issues, par­tic­u­lar­ly periph­er­al neu­ropa­thy and chron­ic pain. Although pre-exist­ing neu­ropa­thy is a risk fac­tor for chron­ic pain, tumor-induced neu­ropa­thy has not been firm­ly estab­lished in pre-clin­i­cal mod­els. Con­sis­tent with clin­i­cal obser­va­tions, we show that mice with col­orec­tal can­cer devel­op periph­er­al neu­ropa­thy, which was asso­ci­at­ed with sub­tle loco­mo­tor deficits, with­out overt hypersensitivity. 

We detect­ed wide­spread dif­fer­ences in pro-inflam­ma­to­ry cytokines and lipid metabo­lites in periph­er­al nerves from tumor-bear­ing mice. Macrophage accu­mu­la­tion, myelin decom­paction and ryan­odine recep­tor oxi­da­tion were asso­ci­at­ed with dys­func­tion­al cal­ci­um home­osta­sis and reduced spike ampli­tude in sen­so­ry neu­rons. Sim­i­lar alter­ations in plas­ma inflam­ma­to­ry medi­a­tors and lipid metabo­lites were asso­ci­at­ed with neu­ropa­thy and macrophage accu­mu­la­tion in periph­er­al nerves of rhe­sus macaques with col­orec­tal cancer. 

Con­sis­tent­ly, mice with col­orec­tal can­cer exhib­it greater pain sen­si­tiv­i­ty fol­low­ing treat­ment with oxali­platin. These find­ings sug­gest col­orec­tal can­cer is causal­ly linked to a sub­a­cute form of chron­ic inflam­ma­to­ry demyeli­nat­ing polyneu­ropa­thy across species, which may rep­re­sent an under-report­ed, yet impor­tant risk fac­tor for neu­ro­log­i­cal dys­func­tion in col­orec­tal can­cer survivors.

Latent Neuropathy in Colorectal Cancer: Implications for Cancer Survivorship
Latent Neuropathy in Colorectal Cancer: Implications for Cancer Survivorship
Latent Neuropathy in Colorectal Cancer: Implications for Cancer Survivorship

Andrew Shep­herd 

Dr. Andrew Shep­herd con­ducts pre­clin­i­cal research inves­ti­gat­ing the mech­a­nisms that link inflam­ma­tion to the pain induced by var­i­ous forms of injury, includ­ing joint dam­age and chemother­a­py-induced neu­ropa­thy, with a par­tic­u­lar empha­sis on sig­nal­ing relat­ed to the renin-angiotensin sys­tem. The ulti­mate goal of the Shep­herd Lab in the Depart­ment of Symp­tom Research is to iden­ti­fy inter­ven­tions that can mit­i­gate or pre­vent the devel­op­ment of pain asso­ci­at­ed with these chron­ic dis­ease states.

Dr. Shep­herd earned his bach­e­lor’s degree in mol­e­c­u­lar cell biol­o­gy in 2003 and a doc­tor­al degree in neu­roim­munomod­u­la­tion in 2006, both from the Uni­ver­si­ty of Man­ches­ter in Great Britain. His train­ing and exper­tise focus on rodent mod­els of pain, behav­ioral read­outs of pain sen­si­tiv­i­ty, and assays of pri­ma­ry rodent and human sen­so­ry-neu­ron function.

Dr. Shep­herd co-chairs MD Ander­son­’s Pain Research Con­sor­tium, a unique plat­form that brings togeth­er clin­i­cal and basic sci­ence pain experts for inter­dis­ci­pli­nary dis­cus­sion, inno­v­a­tive prob­lem-solv­ing, and shap­ing the future of pain management.

Dr. Andrew Shep­herd con­ducts pre­clin­i­cal research inves­ti­gat­ing the mech­a­nisms that link inflam­ma­tion to the pain induced by var­i­ous forms of injury, includ­ing joint dam­age and chemother­a­py-induced neu­ropa­thy, with a par­tic­u­lar empha­sis on sig­nal­ing relat­ed to the renin-angiotensin sys­tem. The ulti­mate goal of the Shep­herd Lab in the Depart­ment of Symp­tom Research is to iden­ti­fy inter­ven­tions that can mit­i­gate or pre­vent the devel­op­ment of pain asso­ci­at­ed with these chron­ic dis­ease states.

TBC

Dr. Shep­herd earned his bach­e­lor’s degree in mol­e­c­u­lar cell biol­o­gy in 2003 and a doc­tor­al degree in neu­roim­munomod­u­la­tion in 2006, both from the Uni­ver­si­ty of Man­ches­ter in Great Britain. His train­ing and exper­tise focus on rodent mod­els of pain, behav­ioral read­outs of pain sen­si­tiv­i­ty, and assays of pri­ma­ry rodent and human sen­so­ry-neu­ron function.

Dr. Shep­herd co-chairs MD Ander­son­’s Pain Research Con­sor­tium, a unique plat­form that brings togeth­er clin­i­cal and basic sci­ence pain experts for inter­dis­ci­pli­nary dis­cus­sion, inno­v­a­tive prob­lem-solv­ing, and shap­ing the future of pain management.

Andrew Shepherd
Andrew Shep­herd, Uni­ver­si­ty of Texas MD Ander­son Can­cer Cen­ter, THE USA

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