Table Of ContentSwarnali Acharyya Editor
The Systemic
Effects
of Advanced
Cancer
A Textbook on Cancer-Associated Cachexia
The Systemic Effects of Advanced Cancer
Swarnali Acharyya
Editor
The Systemic Effects
of Advanced Cancer
A Textbook on Cancer-Associated
Cachexia
Editor
SwarnaliAcharyya
ColumbiaUniversityIrvingMedicalCenter
NewYork,NY,USA
ISBN978-3-031-07272-7 ISBN978-3-031-09518-4 (eBook)
https://doi.org/10.1007/978-3-031-09518-4
#SpringerNatureSwitzerlandAG2022
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Contents
ASystemicViewofMetastaticDisease:Inter-Organ
CrosstalkandTherapeuticImplications. . . . . . . . . . . . . . . . . . .. 1
SwarnaliAcharyya
PartI SystemicRegulationinMetastaticDisease
SystemicRegulationofMetastaticDiseaseby
ExtracellularVesiclesandParticles. . . . . . . . . . . . . . . . . . . . . . .. 9
GangWang,CandiaM.Kenific,GraceLieberman,
HaiyingZhang,andDavidLyden
BoneMetastases:SystemicRegulationandImpactonHost. . . . . . 41
SukanyaSureshandTheresaA.Guise
TargetingMetastaticDisease:Challenges
andNewOpportunities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 51
HaitianHu,ZepingHu,andHanqiuZheng
PartII Cachexia:ADebilitatingSystemicEffectofCancer
SignalingPathwaysThatPromoteMuscleCatabolism
inCachexia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 71
J.E.GildaandS.Cohen
TheRoleofInterleukin-6/GP130CytokinesinCancerCachexia. . . 97
DaeniqueH.A.JengelleyandTeresaA.Zimmers
NF-kBSignalingintheMacroenvironmentof
CancerCachexia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 119
BenjaminR.PryceandDenisC.Guttridge
PartIII Therapy-InducedMuscleWasting
Therapy-InducedToxicitiesAssociatedwiththe
OnsetofCachexia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 139
JoshuaR.Huot,FabrizioPin,andAndreaBonetto
Bone-MuscleCrosstalkinAdvancedCancer
andChemotherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 155
DavidL.Waning
v
vi Contents
PartIV PreventingandTargetingCachexiainCancer
NewDevelopmentsinTargetingCancerCachexia. . . . . . . . .. . .. 171
JaniceMiller,MichaelI.Ramage,andRichardJ.E.Skipworth
Exercise:ACriticalComponentofCachexiaPrevention
andTherapyinCancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 193
EmidioE.Pistilli,HannahE.Wilson,andDavidA.Stanton
A Systemic View of Metastatic Disease:
Inter-Organ Crosstalk and Therapeutic
Implications
Swarnali Acharyya
Abstract
summarizes the various systemic effects of
As cancer progresses, thecommunicationand cancer that are detrimental to the host. The
crosstalk between cancer cells and the tumor design of treatments that can prevent and/or
microenvironment become a key determinant reverse these systemic changes is ultimately
of successful cancer cell growth and survival. expected to improve the quality of life and
These interactions arise through either local survivalofcancerpatients.
contact-mediated signaling or the systemic
releaseofsolublefactors,extracellularvesicles
and particles (EVP) by tumor cells. Systemic
effects that are initiated early during cancer Preface
progression, when cancer cell growth is still Asprimarytumorsevolve,cancercellsareableto
confined to the primary tumor, establish the escape from the tumor and enter the systemic
pre-metastatic niche (PMN). PMN formation circulation. However, the vast majority of these
lays the groundwork for cancer-cell coloniza- cancer cells die, and less than 0.01% are able to
tion of distant organs by altering the extracel- colonize distant organs and generate overt meta-
lular matrix, immune-cell composition, and static lesions [1, 2]. The success of metastatic
vascular permeability of distant organs. colonizationandgrowthdependsoncell-intrinsic
Tumors also independently reprogram host programs in cancer cells as well as on the
physiology and metabolism, which often crosstalk between cancer cells and the distant
results in a debilitating skeletal-muscle- microenvironment [3]. These tumor-
wastingsyndromeknownascachexia.Indeed, microenvironmentcommunicationsareimportant
over80%ofadvancedcancerpatientsdevelop during multiple stages of the invasion-metastasis
cachexia and consequently suffer from cascade and are often mediated by either the
reduced tolerance to anti-neoplastic therapies contact-mediatedsignalingorthereleaseofsolu-
andprematuredeath.Thisintroductorychapter blefactorsandextracellularvesiclesandparticles
(EVPs) from the tumor [4]. But when does this
interaction begin? Studies show that the partner-
S.Acharyya(*)
ship between the tumor and the microenviron-
InstituteforCancerGeneticsandDepartmentofPathology
andCellBiology,ColumbiaUniversity,NewYork,NY, ment evolves early, and is already underway
USA duringtheprimarytumorstage.Infact,signaling
HerbertIrvingComprehensiveCancerCenter,NewYork, molecules from tumors in the form of soluble
NY,USA factorsandEVPsreachdistantorgansevenbefore
e-mail:[email protected]
#SpringerNatureSwitzerlandAG2022 1
S.Acharyya(ed.),TheSystemicEffectsofAdvancedCancer,
https://doi.org/10.1007/978-3-031-09518-4_1
2 S.Acharyya
the cancer cells arrive, a phenomenon known as 1 Author and Text Introductions
pre-metastatic niche (PMN) conditioning
[5]. PMN conditioning has been observed in the Theoverallobjectiveofthistextbookistoprovide
lung, liver, brain, and bone, which are common a comprehensive view of the systemic effects of
sites of metastatic colonization from epithelial cancer with examples of inter-organ crosstalk
tumors[6,7].Byremodelingthevascularperme- andsignaling.
ability, immune milieu, and extracellular matrix Part I of this textbook (Chapters “A Systemic
composition, PMN formation can prime distant View of Metastatic Disease: Inter-Organ
organs and increase the chances of metastatic CrosstalkandTherapeuticImplications;Systemic
success.PMN formationistherefore an example RegulationofMetastaticDiseasebyExtracellular
ofasystemicchangethatisinducedremotelyby
Vesicles and Particles; Bone Metastasis: Sys-
tumors in distant organs without the presence of
temic Regulation and Impact on Host; Targeting
cancercellsinthoseorgans.Thefirstpartofthis
Metastatic Disease: Challenges and New
textbook highlights tumor-initiated systemic Opportunities”) includes discussions by lead
changes in distant organs that can influence the experts in the field of metastasis that highlight
metastatic process, patient prognosis, and treat-
how metastatic disease successfully develops
mentoutcome.
through a web of inter-organ crosstalk. The
following questions are addressed in Part I: Is
The systemic changes that occur during cancer inter-organcrosstalkadeterminantofmetastatic
progressionarenotlimitedtofuturesitesofmet- success?Whichorgansparticipateininter-organ
astaticgrowth.Tumor-derivedsolublefactorsand crosstalk and how is it regulated? Does inter-
EVPsalsoinducesystemicchangesintissuesand organ crosstalk have implications for diagnosis
organs that are almost never inhabited by cancer or treatment of metastatic disease? Is targeting
cells, such as skeletal muscle and adipose tissue. themetastasis-promotinginter-organcrosstalka
Thesesystemiceffectsnegativelyimpactthehost viable option to effectively eliminate metastatic
and often result in a debilitating muscle-wasting disease? The lead author of the second chapter
syndromeknownascachexia.Cachexiaispresent is Dr. David Lyden, a physician-scientist and
in 80% of cancer patients and is associated with ProfessorofPediatricsandCellandDevelopmen-
their decreased tolerance to anti-neoplastic ther- tal Biology at Weill Cornell Medicine.
apy,poorprognosis,andaccelerateddeath.While Dr. Lyden’s pioneering work studying the sys-
it is not clear whether cachexia benefits tumor temiceffectsofcancerledtothediscoveryofthe
growth or merely represents an unintended con- “pre-metastatic niche (PMN)” as a key determi-
sequence of advanced cancer, the combined nant of metastatic success and helped elucidate
targeting of cancer and cachexia is expected to the importance of extracellular vesicles and
improvethequalityoflifeandsurvivalforcancer particles (EVPs) during metastatic development.
patients. The second and third parts of this text- Bothphenomenaarenowwidelyviewedasclas-
book, therefore, highlight the impact of systemic
sicexamplesofsystemicregulationduringmetas-
changesinducedbyadvancedcanceronskeletal tasis. In chapter “Systemic Regulation of
muscleandhowthesechangesnegativelyimpact
Metastatic Disease by Extracellular Vesicles and
muscle signaling, size, and function. Additional Particles”, Dr. Lyden and colleagues describe
topics of discussion include how anti-cancer
PMNformation,whichinvolvestheearlymolec-
therapies can further exacerbate muscle wasting
ular and cellular alterations that are induced by
and how new strategies propose to overcome
primary tumors in distant organs and occur even
both cancer- and therapy-induced muscle
before tumor cells arrive at these organ sites.
wasting.
PMNformationisassociatedwithvascularleaki-
ness, extracellular matrix remodeling, inflamma-
tion, and metabolic reprogramming, all of which
ASystemicViewofMetastaticDisease:Inter-OrganCrosstalkandTherapeuticImplications 3
canpromotesuccessfulcolonizationofincoming In the final chapter of Part I
cancer cells. Dr. Lyden and colleagues subse- (Chapter “Targeting Metastatic Disease:
quently describe the mechanisms by which Challenges and New Opportunities”),
pro-metastatic messages are transmitted between Dr.HanqiuZhengandcolleaguesdiscusscurrent
organs.Onemodeoftransmissionoccursthrough opportunities for targeting metastatic disease.
EVPs, which deliver cancer-cell-derived nucleic Dr.ZhengisanAssociateProfessorintheDepart-
acids, proteins, lipids, and metabolites to mentofBasicMedicalSciencesintheSchoolof
non-cancerous recipient cells. Tumor-derived Medicine at Tsinghua University in Beijing,
EVPscantherebyreprogramtheimmunesystem China. He studies drug resistance and metastasis
and aid in PMN formation. Lastly, Chapter “A in breast cancer. Dr. Zheng and colleagueshigh-
Systemic View of Metastatic Disease: Inter- light several promising anti-metastatic strategies
Organ Crosstalk and Therapeutic Implications” designedtotargetthedifferentstepsofthemeta-
describes the biology of EVPs and discusses staticcascade.Inthischapter,theauthorsdiscuss
their utility as biomarkers for the diagnosis of the effectiveness of immunotherapy, anti-HER2
metastaticdisease,and astherapeutic targetsand therapy and bone-metastasis-targeting
deliverables for metastasis treatment. Beyond approaches in the treatment of advanced cancer.
their role in cancer progression, EVPs can also In this context, the authors discuss the systemic
contributetothepathophysiologyofcachexiaand nature of metastasis and the crosstalk between
other paraneoplastic syndromes, a topic that has tumors and organs that harbor metastatic cells,
alsobeensummarizedinthischapter. which presents further therapeutic challenges.
Chapter “Bone Metastasis: Systemic Regula- Ofrelevancehere,severalmetabolicchangesare
tion and Impact on Host” highlights the multi- associated with cancer progression and metasta-
faceted role of TGF-beta, a cytokine that sis,inboththetumorandthehost.Someofthese
promotes both metastasis and muscle weakness metabolic changes represent vulnerabilities that
through tumor-bone-muscle crosstalk. providenewopportunitiesfortargetingmetastatic
Chapter “Bone Metastasis: Systemic Regulation disease, which are also highlighted in this
and Impact on Host” is written by Dr. Theresa chapter.
Guise,whoisaphysician-scientistandProfessor Part II of this textbook is focused on describ-
in the Division of Internal Medicine at the Uni- ing cachexia, a common systemic effect of
versity of Texas MD Anderson Cancer Center, advanced cancer that is linked to poor prognosis
and Co-Director of the Bone Disease Program. and reduced patient survival. Cachexia isacom-
Dr. Guise has made seminal contributions to our plex metabolic syndrome that is associated with
understanding of bone metastasis and its effects the involuntary loss of skeletal muscle and an
onthemusculoskeletalsystem.Inchapter“Bone active catabolic drive that cannot be reversed
Metastasis: Systemic Regulation and Impact on solely by nutritional support. Patients with
Host”,co-authorsDrs.SukanyaSureshandGuise cachexia experience impaired daily functioning,
describehowcancercellsthathavecolonizedthe decreasedtolerancetoanti-cancertherapies,anda
bone initiate and propagate a vicious cycle that drastic reduction in quality of life and survival.
leadstoincreasedboneresorptionanddestruction There are currently no effective FDA-approved
through the TGF-beta signaling pathway. The therapiestopreventorreversecachexia.
authors discuss therapeutic strategies that can Chapters “Signaling Pathways That Promote
interrupt this vicious cycle and reduce bone Muscle Catabolism in Cachexia; The Role of
metastasis.Thischapteralsohighlightstheability Interleukin-6 Cytokines in Cancer Cachexia;
ofTGF-betatopromotemuscledysfunctiondur- NF-kB Signaling in the Macroenvironment of
ing bone metastasis and outlines the design of Cancer Cachexia” provide the readers with
novelstrategiesforTGF-betapathwayinhibition insights into what drives cachexia. Dr. Shenhav
to block both bone metastasis and muscle weak- Cohen isan Associate Professor inthe Technion
nessforenhancedpatientsurvival. Israel Institute of Technology who studies the
4 S.Acharyya
molecular mechanisms that regulate muscle size Translational Sciences for the Hollings Cancer
andproteolysisduringmusclewasting.Inchapter Center at the Medical University of South
“Signaling Pathways That Promote Muscle Carolina. Dr. Guttridge’s long-term research
Catabolism in Cachexia”, co-authors Drs. focuses on the biology of NF-κB and his group
Jennifer Gilda and Cohen highlight the proteo- hasmadeseminalcontributionsindemonstrating
lytic pathways that activate the degradation of how the NF-κB signaling pathway regulates
soluble and contractile myofibrillar proteins and tumorigenesis, muscle differentiation, and
describe the order of the molecular and cellular cachexia. In chapter “NF-kB Signaling in the
events,aswellasthekeyregulators,driving this Macroenvironment of Cancer Cachexia”,
catabolicprocess. co-authors Drs. Benjamin Pryce and Guttridge
How do you define cachexia? What are highlight how the NF-κB pathway promotes
symptoms of cachexia? Is chronic inflammation both cancer development and muscle wasting.
linked to cachexia? Dr. Teresa Zimmers, Thischapterintroducesthereaderstothecanoni-
Founding Director of the Indiana University cal and non-canonical NF-κB pathway, how
(IU) Simon Cancer Center Cachexia Working NF-κB signaling contributes to normal muscle
Group, and Professor of Surgery at the Indiana development,andhowitisperturbedincachexia.
University School of Medicine, addresses these NF-κB signaling is then discussed in the context
questions in chapter “The Role of Interleukin-6 of pancreatic cancer, in which NF-κB signaling
Cytokines in Cancer Cachexia”. Dr. Zimmers drivestumorigenesisaswellascachexiadevelop-
directs the Cachexia Working Group at the IU ment. Finally, the authors describe the role of
Simon Comprehensive Cancer Center and has NF-κBsignalinginblockingmuscleregeneration
madeseminalcontributionstothefieldofcancer inresponsetotumor-factor-inducedmuscledam-
cachexia. In chapter “The Role of Interleukin-6 age, highlighting how NF-κB signaling
Cytokines in Cancer Cachexia”, co-authors Drs. influences multiple nodes of cancer progression
Daenique Jengelley and Zimmers highlight the andcachexiainthetumormacroenvironment.
role of the interleukin-6 (IL-6) family of For patients with metastatic cancer, localized
cytokinesindriving cachexiabyactivatingcom- surgical options are limited, and systemic
mon downstream signaling pathways involving treatments are needed for targeting the
JAK/STAT, MAPK, and AKT. The authors dis- disseminateddisease.Inthisregard,chemothera-
cuss(a)whichoftheIL-6familymembersinduce peutic agents are commonly used for treating
cachexia in preclinical models, (b) which IL-6 metastatic disease across multiple cancer types.
family members areassociated with clinical can- Chemotherapies kill cancer cells but also induce
cer cachexia, (c) how IL-6 family members trig- damagetonormaltissues.InPartIIIofthistext-
ger cachexia, and (d) the current progress in book, the authors discuss how chemotherapy
targeting cachexia using anti-IL-6 or anti-IL-6R adversely affects the musculoskeletal system,
antibodies in preclinical and clinical studies. causingbonelossandexacerbatingcachexia.
Finally, the authors discuss the strengths of such In chapter “Therapy-Induced Toxicities
anti-cytokine therapies that can reduce both Associated with the Onset of Cachexia”,
tumor burden and cachexia simultaneously, Dr. Andrea Bonetto, an Associate Professor of
thereby improving the quality of life and Surgery at the Indiana School of Medicine and
prolongingthesurvivalofcancerpatients. an expert in therapy-induced cachexia, discusses
Among inflammation-associated pathways, chemotherapy-induced toxicities. In particular,
the nuclear factor kappa B (NF-κB) signaling Dr.Bonettoandcolleaguesdiscusswhichchemo-
pathway plays a key role in both tumorigenesis therapeutic agents cause muscle wasting and/or
and cachexia. Dr. Denis Guttridge is a leader in bone loss, which pathways are activated in mus-
thefieldofcancercachexia.HeisaProfessorand cle and bone in response to treatment with che-
the Director of the Darby Children’s Research motherapeutic agents, and strategies that have
Institute and the Associate Director of been designed to counteract these
