Mathematical Modelling as a Proof of Concept for MPNs as a Human Inflammation Model for Cancer Development

Morten Andersen, Zamra Sajid, Rasmus Kristoffer Pedersen, Johanne Gudmand-Høyer, Christina Ellervik, Vibe Skov, Lasse Kjær, Niels Pallisgaard, Torben Kruse, Mads Thomassen, Jesper Thorvald Troelsen, Hans Hasselbalch, Johnny T. Ottesen

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

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.
Original languageEnglish
Article numbere0183620
JournalP L o S One
Volume12
Issue number8
ISSN1932-6203
DOIs
Publication statusPublished - 2017

Cite this

Andersen, Morten ; Sajid, Zamra ; Pedersen, Rasmus Kristoffer ; Gudmand-Høyer, Johanne ; Ellervik, Christina ; Skov, Vibe ; Kjær, Lasse ; Pallisgaard, Niels ; Kruse, Torben ; Thomassen, Mads ; Troelsen, Jesper Thorvald ; Hasselbalch, Hans ; Ottesen, Johnny T. / Mathematical Modelling as a Proof of Concept for MPNs as a Human Inflammation Model for Cancer Development. In: P L o S One. 2017 ; Vol. 12, No. 8.
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title = "Mathematical Modelling as a Proof of Concept for MPNs as a Human Inflammation Model for Cancer Development",
abstract = "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.",
author = "Morten Andersen and Zamra Sajid and Pedersen, {Rasmus Kristoffer} and Johanne Gudmand-H{\o}yer and Christina Ellervik and Vibe Skov and Lasse Kj{\ae}r and Niels Pallisgaard and Torben Kruse and Mads Thomassen and Troelsen, {Jesper Thorvald} and Hans Hasselbalch and Ottesen, {Johnny T.}",
year = "2017",
doi = "10.1371/journal.pone.0183620",
language = "English",
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Mathematical Modelling as a Proof of Concept for MPNs as a Human Inflammation Model for Cancer Development. / Andersen, Morten; Sajid, Zamra; Pedersen, Rasmus Kristoffer; Gudmand-Høyer, Johanne; Ellervik, Christina; Skov, Vibe; Kjær, Lasse; Pallisgaard, Niels ; Kruse, Torben; Thomassen, Mads; Troelsen, Jesper Thorvald; Hasselbalch, Hans; Ottesen, Johnny T.

In: P L o S One, Vol. 12, No. 8, e0183620, 2017.

Research output: Contribution to journalJournal articleResearchpeer-review

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 Kristoffer

AU - Gudmand-Høyer, Johanne

AU - Ellervik, Christina

AU - Skov, Vibe

AU - Kjær, Lasse

AU - Pallisgaard, Niels

AU - Kruse, Torben

AU - Thomassen, Mads

AU - Troelsen, Jesper Thorvald

AU - Hasselbalch, Hans

AU - Ottesen, Johnny T.

PY - 2017

Y1 - 2017

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

VL - 12

JO - P L o S One

JF - P L o S One

SN - 1932-6203

IS - 8

M1 - e0183620

ER -