Mathematical modelling as a proof of concept for MPNs as a human inflammation model for cancer development

TY - JOUR

T1 - Mathematical modelling as a proof of concept for MPNs as a human inflammation model for cancer development

AU - Andersen, Morten

AU - Sajid, Zamra

AU - Pedersen, Rasmus K.

AU - Gudmand-hoeyer, Johanne

AU - Ellervik, Christina

AU - Skov, Vibe

AU - Kjær, Lasse

AU - Pallisgaard, Niels

AU - Kruse, Torben A.

AU - Thomassen, Mads

AU - Troelsen, Jesper

AU - Hasselbalch, Hans Carl

AU - Ottesen, Johnny T.

PY - 2017/8

Y1 - 2017/8

N2 - The chronic Philadelphia-negative myeloproliferative neoplasms (MPNs) are acquired stem cell neoplasms which ultimately may transform to acute myelogenous leukemia. Most recently, chronic inflammation has been described as an important factor for the development and progression of MPNs in the biological continuum from early cancer stage to the advanced myelofibrosis stage, the MPNs being described as “A Human Inflammation Model for Cancer Development“. This novel concept has been built upon clinical, experimental, genomic, immunological and not least epidemiological studies. Only a few studies have described the development of MPNs by mathematical models, and none have addressed the role of inflammation for clonal evolution and disease progression. Herein, we aim at using mathematical modelling to substantiate the concept of chronic inflammation as an important trigger and driver of MPNs.The basics of the model describe the proliferation from stem cells to mature cells including mutations of healthy stem cells to become malignant stem cells. We include a simple inflammatory coupling coping with cell death and affecting the basic model beneath. First, we describe the system without feedbacks or regulatory interactions. Next, we introduce inflammatory feedback into the system. Finally, we include other feedbacks and regulatory interactions forming the inflammatory-MPN model. Using mathematical modeling, we add further proof to the concept that chronic inflammation may be both a trigger of clonal evolution and an important driving force for MPN disease progression. Our findings support intervention at the earliest stage of cancer development to target the malignant clone and dampen concomitant inflammation.

AB - The chronic Philadelphia-negative myeloproliferative neoplasms (MPNs) are acquired stem cell neoplasms which ultimately may transform to acute myelogenous leukemia. Most recently, chronic inflammation has been described as an important factor for the development and progression of MPNs in the biological continuum from early cancer stage to the advanced myelofibrosis stage, the MPNs being described as “A Human Inflammation Model for Cancer Development“. This novel concept has been built upon clinical, experimental, genomic, immunological and not least epidemiological studies. Only a few studies have described the development of MPNs by mathematical models, and none have addressed the role of inflammation for clonal evolution and disease progression. Herein, we aim at using mathematical modelling to substantiate the concept of chronic inflammation as an important trigger and driver of MPNs.The basics of the model describe the proliferation from stem cells to mature cells including mutations of healthy stem cells to become malignant stem cells. We include a simple inflammatory coupling coping with cell death and affecting the basic model beneath. First, we describe the system without feedbacks or regulatory interactions. Next, we introduce inflammatory feedback into the system. Finally, we include other feedbacks and regulatory interactions forming the inflammatory-MPN model. Using mathematical modeling, we add further proof to the concept that chronic inflammation may be both a trigger of clonal evolution and an important driving force for MPN disease progression. Our findings support intervention at the earliest stage of cancer development to target the malignant clone and dampen concomitant inflammation.

U2 - 10.1371/journal.pone.0183620

DO - 10.1371/journal.pone.0183620

M3 - Journal article

C2 - 28859112

SN - 1932-6203

VL - 12

JO - PLOS ONE

JF - PLOS ONE

IS - 8

M1 - e0183620

ER -