Systems Biology of Tumor Microenvironment: Quantitative Modeling and Simulations

264 Pages·2016·13.22 MB·English

by  Katarzyna A. Rejniak (eds.)

Advances in Experimental Medicine and Biology 936
Katarzyna A. Rejniak Editor
Systems Biology
of Tumor
Microenvironment
Quantitative Modeling and Simulations
Advances in Experimental Medicine
and Biology
Volume 936
EditorialBoard
IRUNR.COHEN,TheWeizmannInstituteofScience,Rehovot,Israel
N.S.ABELLAJTHA,KlineInstituteforPsychiatricResearch,Orangeburg,
NY,USA
JOHND.LAMBRIS,UniversityofPennsylvania,Philadelphia,PA,USA
RODOLFOPAOLETTI,UniversityofMilan,Milan,Italy
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Katarzyna A. Rejniak
Editor
Systems Biology
of Tumor
Microenvironment
Quantitative Modeling
and Simulations
123
Editor
KatarzynaA.Rejniak
IntegratedMathematicalOncologyDepartment
H.LeeMoffittCancerCenterandResearchInstitute
Tampa,FL,USA
ISSN0065-2598 ISSN2214-8019 (electronic)
AdvancesinExperimentalMedicineandBiology
ISBN978-3-319-42021-9 ISBN978-3-319-42023-3 (eBook)
DOI10.1007/978-3-319-42023-3
LibraryofCongressControlNumber:2016955061
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Foreword
Despite recent advances in the development of new targeted anticancer
therapies, further efforts are necessary to account for the elusive behavior
ofcancercellsinvolvingtumorheterogeneityanditsassociatedstromaofthe
tumormicroenvironment,whichareprovidingcontinuouschallengesforthe
designofneweffectiveanti-tumortherapies.
Anewapproachtounderstandingcancerbiologyanddesigningmoreef-
fectivetherapiesismathematicalmodeling.Mathematicalmodelsarehighly
adaptable tools to deconvolute the complex, multidimensional datasets and
makethemamenabletoanalysisfromdifferentangles.Theresultsfromsuch
studiesmaybeinstrumentalinmakingthisstepforward.
Thereisamultitudeoftumorandmicroenvironment-associatedsignaling
molecules, which include numerous cytokines, growth factors, hormones,
proteolytic enzymes such as metalloproteinases and metabolic components
produced both by the tumor cells and the tumor-associated stroma [10, 18].
Thesecomponentsinteractwiththetumorcellsandthestromalcells,thereby
affecting tumor cell migration and invasion into nearby tissue or leading to
the metastatic tumor spread into blood as circulating tumor cells, and into
distantorgans.
The process of invasion and migration through the extracellular matrix
(ECM)isaidedbynumerousECMstructuralcomponentsthatincludevarious
fibrouselementssuchascollagens,fibronectin,lamininandmanyothers.In
addition,theabundanceofspace-fillingcomponentsincludingglycosamino-
glycans (GAGs) and attached proteoglycans (PGs) [19, 20] provide a rich
microenvironment for the tumor cells to migrate through the extracellular
matrix. In fact, it was shown that these structural ECM components and
their increased rigidity actually promote migration of tumor cells such as
glioma[12].
In addition to the ECM signaling molecules and the structural ECM
elements, the tumor microenvironment also contains stromal cells such as
fibroblasts and endothelial cells as well as pericytes of the angiogenic
tumor vasculature. Also, cells of immune system such as mononuclear
cells; monocytes and their derivative macrophages; granulocytes including
neutrophils, eosinophils, basophils and mast cells, and also B and T lym-
phocytes are found in the tumor microenvironment. These cells can interact
to the certain degree with tumor antigens and secrete various signaling
molecules.Itisnowknownthatpresenceofthesecellsinthetumorvicinity
v
vi Foreword
would indicate an “inflamed” status of the tumor expressing Programmed
DeathLigand-1(PD-L1)andresultinginabetterpatientprognosiscompared
to“non-inflamed”tumors”[5].
The issue of quiescent tumor cell populations, often termed cancer stem
cells, provides yet another challenge for designing new and effective ther-
apeutic approaches. These quiescent cell populations frequently require a
specific microenvironment, a perivascular and hypoxic niche to keep their
“stemness” with few antigenic markers. As a consequence, these cells are
difficult to target by any therapeutic approaches. Furthermore, variations in
stemcells’behaviorduetoheterogeneityofthetumormicroenvironmentmay
contributetothegeneticheterogeneityofthetumor[6].
Based on the complexity of the tumor microenvironment, therapeutic
agents targeting tumors must overcome a variety of hurdles like capture by
multiple ECM components, leaky blood vessels within tumors, the tumor
intestinalfluidpressurecausedbyaccumulationofinflammatorycomponents
andahypoxicenvironment.Theroleofhypoxiainthetumormicroenviron-
ment and its contribution to immune resistance and immune suppression is
already well documented [9]. In addition, any targeting therapeutics would
have to reach the target at a sufficient therapeutic concentration to have a
therapeuticeffect.
Oneoftheexamplesthatcanbeusedtoportraythetumormicroenviron-
ment complexity and its significance for a therapeutics delivery- is glioma,
with glioblastoma (GBM) being the most advanced subtype. It is a primary
brain tumor with highly invasive characteristics and short (6 months to
2years)patientsurvivaltime(reviewedby[19]).ThemainECMcomponents
of glioma, which invades brain parenchyma just within centimeters from
a lesion [2] are the GAG hyaluronan (HA) and PGs such as chondroitin
sulfate proteoglycans CSPGs) and heparan sulfate proteoglycans (HSPGs).
All of these molecules play important roles in cell signaling and migration
[16].Inaddition,HAwasrecognizedasmainECMcomponentthatformsa
microenvironmentinwhichstemcellscanundergoself-renewal[4].
The HA receptor CD44 adhesion molecule, is highly expressed on the
leadingedgeofgliomaattheinterfacewiththenormalbraintissuesignifying
the importance of these ECM molecules in glioma invasion [13, 15, 17,
18, 20, 21]. It was found recently that HA and its CD44 receptor may
play an important role in the “stemness” and survival of cancer stem cells
[4]. In addition, CSPG proteoglycan known as neuroglial protein-2 (NG2)
wasrecognizedasacellbiomarkerforoligodendrocyteprogenitorcellsand
foundingliomas[11,14],thereforeemphasizingtheimportanceofthisECM
molecule.
TheHSPGscomponentsofthegliomamicroenvironmentarealsopartof
bloodvesselsandserveasalocationforgrowthfactorandcytokinestorage,
therefore contributing to the creation of a niche in which glioma stem cells
can receive signals from its microenvironment [3]. The blood vessels and
myelinatednervefiberswhichserveastheinfiltrativepathfordisseminating
glioma cells have higher rigidity and together with the increased rigidity of
ECMcontributetogliomamigration[8,12].
Foreword vii
Recent therapeutic approaches to glioma and other tumors already take
into account the importance of cancer stem cells and their niches [7]. In
addition, detection of circulating tumor cells in blood of cancer patients,
includinggliomapatientsareviewedas“Liquidbiopsies”thathavethehigh
clinicalimportanceintumordiagnosisandfollowup[1].
Overall, the complexity of the tumor and tumor microenvironment and
their multiple interactive processes could only be better understood and
targetedwhennewanalyticalmethodssuchasmathematicalmodelingcould
be applied to understand this highly complex system. This could aid in the
development ofnewtherapeuticstrategiesthatcanaccountforandpossibly
unravelsomeofthecomplexandelusivebehaviorofcancer.
Tampa,FL,USA MarzennaWiranowska
April2016
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Preface
Thecomplexityandheterogeneityoftumormicroenvironment,aswellasits
dynamic interactions with tumor cells are a very attractive topic for math-
ematical modeling. Several quite diverse modeling approaches have been
developed over the last couple of years to address the role of the microen-
vironment intumor initiation,progression and itsresponse totreatments. In
order to provide the readers both biologically- and mathematically-oriented
withtherecentachievementsinthisarea,Iinvitedseveralresearcherstoshare
their mathematical and computational models of tumor microenvironment
andtheirperspectivesonthefutureofthisfield.
Both normal and tumor cells are embedded into a complex and dynam-
ically changing environment. That environment can regulate the behavior
of individual cells and modulate homeostatic balance of the whole tissue.
The complexity of tumor microenvironment arises from multiple players
that interact with one another. Various types of cells reside in or migrate
through the tumor stroma, including endothelial cells and pericytes forming
the capillaries; immune cells, such as T cells, B cells, or macrophages; as
wellasadipocytes,fibroblastandotherstromalcells.Theextracellularmatrix
proteins (collagen, elastin, fibronectin, laminin) form fibril meshes defining
theirorientation,stiffnessandoverallphysicalcharacteristics.Theinterstitial
fluidthatpenetratesspacebetweenthecellsandthefibersallowsfordiffusion
of numerous chemical factors (nutrients, oxygen, glucose, growth factors,
chemokines, matrix metalloproteinases) and enable their transport to all
stromalcomponents.
Atallstagesoftumordevelopmentfrominitiationtogrowthandinvasion,
to metastasis, the tumor cells are subjected to cues and interactions from
the surrounding microenvironment, and also modulate the environment in
their vicinity. Additionally, when a given treatment (i.e., surgery, chemo-,
radio-,immune-hormoneorcombinationtherapy)isapplied,thetumorand
its microenvironment may undergo significant alterations. As a result, the
microenvironmental selection forces and tumor physico-chemical landscape
mayshift.
Duetothecomplexity,heterogeneity,anddynamicchangesthattakeplace
inthetumormicroenvironment,itisdifficulttoinvestigateexperimentally,in
a precise and quantitative way, all potential interactions between the tumor
and its surrounding stroma. Thus, laboratory experiments are designed to
address these issues at different scales of complexity. For example, genetic
modifications, protein interactions, signaling pathways, cellular phenotypic
ix