Abstract
Obesity is a proven risk factor and a debated prognostic factor in renal cell carcinoma (RCC). Termed as an “obesity paradox,” the topic has churned controversies, with a few arguing of no true biological association. Suggesting otherwise, a few studies revealed adiposity-induced altered molecular and transcriptomic signatures, at both the systemic and local (tumor and peritumoral adipose tissue) levels, in RCC patients, favoring the paradox. Summarizing such studies suggests of a considerable biological support to adiposity as a promising prognostic factor in RCC patients, although much needs to be clarified before adopting it as a valuable addition to the existing prognostic model.
References
1.
WHO Expert Consultation
. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies
. Lancet
. 2004 Jan 10
;363
(9403
):157
–63
. 2.
Kyrou
I
, Randeva
HS
, Tsigos
C
, Kaltsas
G
, Weickert
MO
. Clinical problems caused by obesity
. In: Feingold
KR
, Anawalt
B
, Boyce
A
, Chrousos
G
, Dungan
K
, Grossman
A
, et al., editors. Endotext
. South Dartmouth (MA)
: MDText.com, Inc.
; 2000
.3.
Budny
A
, Grochowski
C
, Kozłowski
P
, Kolak
A
, Kamińska
M
, Budny
B
, et al. Obesity as a tumour development triggering factor
. Ann Agric Environ Med
. 2019 Mar 22
;26
(1
):13
–23
. 4.
Lauby-Secretan
B
, Scoccianti
C
, Loomis
D
, Grosse
Y
, Bianchini
F
, Straif
K
. Body fatness and cancer: viewpoint of the IARC working group
. N Engl J Med
. 2016 Aug 25
;375
(8
):794
–8
. 5.
Lee
DH
, Giovannucci
EL
. The obesity paradox in cancer: epidemiologic insights and perspectives
. Curr Nutr Rep
. 2019 Sep
;8
(3
):175
–81
. 6.
Siegel
RL
, Fedewa
SA
, Miller
KD
, Goding-Sauer
A
, Pinheiro
PS
, Martinez-Tyson
D
, et al. Cancer statistics for Hispanics/Latinos, 2015, 2019
. CA Cancer J Clin
. 2019 Jan
;65
(6
):457
–80
. 7.
McGuire
BB
, Fitzpatrick
JM
. BMI and the risk of renal cell carcinoma
. Curr Opin Urol
. 2011 Sep
;21
(5
):356
–61
. 8.
Häggström
C
, Rapp
K
, Stocks
T
, Manjer
J
, Bjørge
T
, Ulmer
H
, et al. Metabolic factors associated with risk of renal cell carcinoma
. PLoS One
. 2013
;8
(2
):e57475
. 9.
Johansson
M
, Carreras-Torres
R
, Scelo
G
, Purdue
MP
, Mariosa
D
, Muller
DC
, et al. The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study
. PLoS Med
. 2019 Jan
;16
(1
):e1002724
.10.
Gan
CL
, Heng
DYC
. New insights into the obesity paradox in renal cell carcinoma
. Nat Rev Nephrol
. 2020 May
;16
(5
):253
–4
. 11.
Baracos
VE
, Arribas
L
. Sarcopenic obesity: hidden muscle wasting and its impact for survival and complications of cancer therapy
. Ann Oncol
. 2018 Feb 1
;29
(Suppl_2
):ii1
–9
.12.
Horiguchi
A
, Asano
T
, Asano
T
, Ito
K
, Sumitomo
M
, Hayakawa
M
. Fatty acid synthase over expression is an indicator of tumor aggressiveness and poor prognosis in renal cell carcinoma
. J Urol
. 2008 Sep
;180
(3
):1137
–40
. 13.
Sanchez
A
, Furberg
H
, Kuo
F
, Vuong
L
, Ged
Y
, Patil
S
, et al. Transcriptomic signatures related to the obesity paradox in patients with clear cell renal cell carcinoma: a cohort study
. Lancet Oncol
. 2020 Feb
;21
(2
):283
–93
. 14.
Coelho
M
, Oliveira
T
, Fernandes
R
. Biochemistry of adipose tissue: an endocrine organ
. Arch Med Sci
. 2013 Apr 20
;9
(2
):191
–200
. 15.
Aurilio
G
, Piva
F
, Santoni
M
, Cimadamore
A
, Sorgentoni
G
, Lopez-Beltran
A
, et al. The role of obesity in renal cell carcinoma patients: clinical-pathological implications
. Int J Mol Sci
. 2019 Nov 13
;20
(22
):5683
.16.
Quail
DF
, Dannenberg
AJ
. The obese adipose tissue microenvironment in cancer development and progression
. Nat Rev Endocrinol
. 2019 Mar
;15
(3
):139
–54
. 17.
Grossmann
ME
, Cleary
MP
. The balance between leptin and adiponectin in the control of carcinogenesis: focus on mammary tumorigenesis
. Biochimie
. 2012 Oct
;94
(10
):2164
–71
. 18.
Considine
RV
, Sinha
MK
, Heiman
ML
, Kriauciunas
A
, Stephens
TW
, Nyce
MR
, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans
. N Engl J Med
. 1996 Feb 1
;334
(5
):292
–5
. 19.
Arita
Y
, Kihara
S
, Ouchi
N
, Takahashi
M
, Maeda
K
, Miyagawa
J
, et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity
. Biochem Biophys Res Commun
. 1999 Apr 2
;257
(1
):79
–83
. 20.
Horiguchi
A
, Ito
K
, Sumitomo
M
, Kimura
F
, Asano
T
, Hayakawa
M
. Decreased serum adiponectin levels in patients with metastatic renal cell carcinoma
. Jpn J Clin Oncol
. 2008 Feb
;38
(2
):106
–11
. 21.
Park
J
, Morley
TS
, Kim
M
, Clegg
DJ
, Scherer
PE
. Obesity and cancer: mechanisms underlying tumour progression and recurrence
. Nat Rev Endocrinol
. 2014 Aug
;10
(8
):455
–65
. 22.
Kamada
Y
, Matsumoto
H
, Tamura
S
, Fukushima
J
, Kiso
S
, Fukui
K
, et al. Hypoadiponectinemia accelerates hepatic tumor formation in a nonalcoholic steatohepatitis mouse model
. J Hepatol
. 2007 Oct
;47
(4
):556
–64
. 23.
Arner
E
, Forrest
AR
, Ehrlund
A
, Mejhert
N
, Itoh
M
, Kawaji
H
, et al. Ceruloplasmin is a novel adipokine which is overexpressed in adipose tissue of obese subjects and in obesity-associated cancer cells
. PLoS One
. 2014
;9
(3
):e80274
. 24.
Greenhill
C
. A-FABP links obesity and breast cancer
. Nat Rev Endocrinol
. 2018 Oct
;14
(10
):566
.25.
Hao
J
, Zhang
Y
, Yan
X
, Yan
F
, Sun
Y
, Zeng
J
, et al. Circulating adipose fatty acid binding protein is a new link underlying obesity-associated breast/mammary tumor development
. Cell Metab
. 2018 Nov 6
;28
(5
):689
–705
. 26.
Brestoff
JR
, Artis
D
. Immune regulation of metabolic homeostasis in health and disease
. Cell
. 2015 Mar 26
;161
(1
):146
–60
. 27.
Maihöfner
C
, Charalambous
MP
, Bhambra
U
, Lightfoot
T
, Geisslinger
G
, Gooderham
NJ
. Expression of cyclooxygenase-2 parallels expression of interleukin-1beta, interleukin-6 and NF-kappaB in human colorectal cancer
. Carcinogenesis
. 2003 Apr
;24
(4
):665
–71
. 28.
Osório-Costa
F
, Carvalheira
JBC
. TNF-α in obesity-associated colon cancer
. Transl Gastrointest Cancer
. 2013
;2
(4
):179
–93
.29.
Westley
RL
, May
FE
. A twenty-first century cancer epidemic caused by obesity: the involvement of insulin, diabetes, and insulin-like growth factors
. Int J Endocrinol
. 2013
;2013
:632461
. 30.
Ougolkov
AV
, Bone
ND
, Fernandez-Zapico
ME
, Kay
NE
, Billadeau
DD
. Inhibition of glycogen synthase kinase-3 activity leads to epigenetic silencing of nuclear factor kappaB target genes and induction of apoptosis in chronic lymphocytic leukemia B cells
. Blood
. 2007
;110
(2
):735
–42
. 31.
Björndahl
M
, Cao
R
, Nissen
LJ
, Clasper
S
, Johnson
LA
, Xue
Y
, et al. Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo
. Proc Natl Acad Sci U S A
. 2005
;102
(43
):15593
–8
. 32.
Chen
SI
, Hsieh
CC
. Why are women with obesity more likely to develop breast cancer
. Future Oncol
. 2018 Jul
;14
(16
):1523
–6
. 33.
Howe
LR
, Subbaramaiah
K
, Hudis
CA
, Dannenberg
AJ
. Molecular pathways: adipose inflammation as a mediator of obesity-associated cancer
. Clin Cancer Res
. 2013 Nov 15
;19
(22
):6074
–83
. 34.
Balaban
S
, Lee
LS
, Schreuder
M
, Hoy
AJ
. Obesity and cancer progression: is there a role of fatty acid metabolism?
Biomed Res Int
. 2015
;2015
:274585
. 35.
Setiawan
VW
, Stram
DO
, Nomura
AM
, Kolonel
LN
, Henderson
BE
. Risk factors for renal cell cancer: the multiethnic cohort
. Am J Epidemiol
. 2007 Oct 15
;166
(8
):932
–40
. 36.
Dobbins
M
, Decorby
K
, Choi
BC
. The association between obesity and cancer risk: a meta-analysis of observational studies from 1985 to 2011
. ISRN Prev Med
. 2013
;2013
:680536
. 37.
Adams
KF
, Leitzmann
MF
, Albanes
D
, Kipnis
V
, Moore
SC
, Schatzkin
A
, et al. Body size and renal cell cancer incidence in a large US cohort study
. Am J Epidemiol
. 2008 Aug 1
;168
(3
):268
–77
. 38.
Bertrand
LA
, Thomas
LJ
, Li
P
, Buchta
CM
, Boi
SK
, Orlandella
RM
, et al. Obesity as defined by waist circumference but not body mass index is associated with higher renal mass complexity
. Urol Oncol
. 2017 Nov
;35
(11
):661.e1
–e6
. 39.
De Pergola
G
, Campobasso
N
, Nardecchia
A
, Triggiani
V
, Caccavo
D
, Gesualdo
L
, et al. Para- and perirenal ultrasonographic fat thickness is associated with 24-hours mean diastolic blood pressure levels in overweight and obese subjects
. BMC Cardiovasc Disord
. 2015 Sep 30
;15
:108
. 40.
Wang
Q
, Tu
H
, Zhu
M
, Liang
D
, Ye
Y
, Chang
DW
, et al. Circulating obesity-driven biomarkers are associated with risk of clear cell renal cell carcinoma: a two-stage, case-control study
. Carcinogenesis
. 2019 Oct 16
;40
(10
):1191
–7
. 41.
Kamat
AM
, Shock
RP
, Naya
Y
, Rosser
CJ
, Slaton
JW
, Pisters
LL
. Prognostic value of body mass index in patients undergoing nephrectomy for localized renal tumors
. Urology
. 2004 Jan
;63
(1
):46
–50
. 42.
Choi
Y
, Park
B
, Jeong
BC
, Seo
SI
, Jeon
SS
, Choi
HY
, et al. Body mass index and survival in patients with renal cell carcinoma: a clinical-based cohort and meta-analysis
. Int J Cancer
. 2013 Feb 1
;132
(3
):625
–34
. 43.
Albiges
L
, Hakimi
AA
, Xie
W
, McKay
RR
, Simantov
R
, Lin
X
, et al. Body mass index and metastatic renal cell carcinoma: clinical and biological correlations
. J Clin Oncol
. 2016 Oct 20
;34
(30
):3655
–63
. 44.
Wilson
KM
, Cho
E
. Obesity and kidney cancer
. Recent Results Cancer Res
. 2016
;208
:81
–93
. 45.
Jespersen
NZ
, Feizi
A
, Andersen
ES
, Heywood
S
, Hattel
HB
, Daugaard
S
, et al. Heterogeneity in the perirenal region of humans suggests presence of dormant brown adipose tissue that contains brown fat precursor cells
. Mol Metab
. 2019 Jun
;24
:30
–43
. 46.
Li
X
, Wang
G
, Liu
J
, Ding
G
. Increased UCP1 expression in the perirenal adipose tissue of patients with renal cell carcinoma
. Oncol Rep
. 2019 Nov
;42
(5
):1972
–80
.47.
Zi
X
, Lusch
A
, Blair
CA
, Okhunov
Z
, Yokoyama
NN
, Liu
S
, et al. Effect of perineoplasm perinephric adipose tissues on migration of clear cell renal cell carcinoma cells: a potential role of WNT signaling
. Oncotarget
. 2016 Aug 16
;7
(33
):53277
–88
. 48.
Ito
R
, Narita
S
, Huang
M
, Nara
T
, Numakura
K
, Takayama
K
, et al. The impact of obesity and adiponectin signaling in patients with renal cell carcinoma: a potential mechanism for the “obesity paradox”
. PLoS One
. 2017
;12
(2
):e0171615
. 49.
Hu
CY
, Mohtat
D
, Yu
Y
, Ko
YA
, Shenoy
N
, Bhattacharya
S
, et al. Kidney cancer is characterized by aberrant methylation of tissue-specific enhancers that are prognostic for overall survival
. Clin Cancer Res
. 2014 Aug 15
;20
(16
):4349
–60
. 50.
Peters
I
, Gebauer
K
, Dubrowinskaja
N
, Atschekzei
F
, Kramer
MW
, Hennenlotter
J
, et al. GATA5 CpG island hypermethylation is an independent predictor for poor clinical outcome in renal cell carcinoma
. Oncol Rep
. 2014 Apr
;31
(4
):1523
–30
. 51.
Mendoza-Pérez
J
, Gu
J
, Herrera
LA
, Tannir
NM
, Zhang
S
, Matin
S
, et al. Prognostic significance of promoter CpG island methylation of obesity-related genes in patients with nonmetastatic renal cell carcinoma
. Cancer
. 2017 Sep 15
;123
(18
):3617
–27
. 52.
Abdu Allah
AM
, El-Hefnway
SM
, Alhanafy
AM
, Zahran
AM
, Kasem
HE
. Leptin receptor gene (A/G) polymorphism rs1137101 and renal cell carcinoma
. Mol Cell Biochem
. 2018 Nov
;448
(1–2
):137
–44
. 53.
Shen
K
, Vesey
DA
, Hasnain
SZ
, Zhao
KN
, Wang
H
, Johnson
DW
, et al. A cost-effective three-dimensional culture platform functionally mimics the adipose tissue microenvironment surrounding the kidney
. Biochem Biophys Res Commun
. 2020 Feb 12
;522
(3
):736
–42
. 54.
Komohara
Y
, Hasita
H
, Ohnishi
K
, Fujiwara
Y
, Suzu
S
, Eto
M
, et al. Macrophage infiltration and its prognostic relevance in clear cell renal cell carcinoma
. Cancer Sci
. 2011 Jul
;102
(7
):1424
–31
. 55.
Kovaleva
OV
, Samoilova
DV
, Shitova
MS
, Gratchev
A
. Tumor associated macrophages in kidney cancer
. Anal Cell Pathol
. 2016
;2016
:9307549
. 56.
Donat
SM
, Salzhauer
EW
, Mitra
N
, Yanke
BV
, Snyder
ME
, Russo
P
. Impact of body mass index on survival of patients with surgically treated renal cell carcinoma
. J Urol
. 2006 Jan
;175
(1
):46
–52
. 57.
Jeon
HG
, Jeong
IG
, Lee
JH
, Lee
CJ
, Kwak
C
, Kim
HH
, et al. Prognostic value of body mass index in Korean patients with renal cell carcinoma
. J Urol
. 2010 Feb
;183
(2
):448
–54
. 58.
Waalkes
S
, Merseburger
AS
, Kramer
MW
, Herrmann
TR
, Wegener
G
, Rustemeier
J
, et al. Obesity is associated with improved survival in patients with organ-confined clear-cell kidney cancer
. Cancer Causes Control
. 2010 Nov
;21
(11
):1905
–10
. 59.
Rogde
AJ
, Gudbrandsdottir
G
, Hjelle
KM
, Sand
KE
, Bostad
L
, Beisland
C
. Obesity is associated with an improved cancer-specific survival, but an increased rate of postoperative complications after surgery for renal cell carcinoma
. Scand J Urol Nephrol
. 2012 Oct
;46
(5
):348
–57
. 60.
Zhang
J
, Chen
Q
, Li
ZM
, Xu
XD
, Song
AF
, Wang
LS
. Association of body mass index with mortality and postoperative survival in renal cell cancer patients, a meta-analysis
. Oncotarget
. 2018 Mar 2
;9
(17
):13959
–70
. 61.
Choueiri
TK
, Xie
W
, Kollmannsberger
CK
, Rini
BI
, McDermott
DF
, Knox
JJ
, et al. The impact of body mass index (BMI) and body surface area (BSA) on treatment outcome to vascular endothelial growth factor (VEGF)-targeted therapy in metastatic renal cell carcinoma: results from a large international collaboration
. J Clin Oncol
. 2010
;28
(15_Suppl
):4524
–4
. 62.
Steffens
S
, Grünwald
V
, Ringe
KI
, Seidel
C
, Eggers
H
, Schrader
M
, et al. Does obesity influence the prognosis of metastatic renal cell carcinoma in patients treated with vascular endothelial growth factor-targeted therapy?
Oncologist
. 2011
;16
(11
):1565
–71
. 63.
Ladoire
S
, Bonnetain
F
, Gauthier
M
, Zanetta
S
, Petit
JM
, Guiu
S
, et al. Visceral fat area as a new independent predictive factor of survival in patients with metastatic renal cell carcinoma treated with antiangiogenic agents
. Oncologist
. 2011
;16
(1
):71
–81
. 64.
Mizuno
R
, Miyajima
A
, Hibi
T
, Masuda
A
, Shinojima
T
, Kikuchi
E
, et al. Impact of baseline visceral fat accumulation on prognosis in patients with metastatic renal cell carcinoma treated with systemic therapy
. Med Oncol
. 2017 Apr
;34
(4
):47
. 65.
Martini
DJ
, Shabto
JM
, Liu
Y
, Carthon
BC
, Speak
A
, Hitron
E
, et al. Body mass index (BMI) and toxicities and association with clinical outcomes (CO) in metastatic renal cell carcinoma (mRCC) patients (pts) treated with cabozantinib (cabo)
. J Clin Oncol
. 2019
;37
(7_Suppl
):613
–3
.66.
Hakimi
AA
, Voss
MH
, Kuo
F
, Sanchez
A
, Liu
M
, Nixon
BG
, et al. Transcriptomic profiling of the tumor microenvironment reveals distinct subgroups of clear cell renal cell cancer: data from a randomized phase III trial
. Cancer Discov
. 2019 Apr
;9
(4
):510
–25
. 67.
McDermott
DF
, Huseni
MA
, Atkins
MB
, Motzer
RJ
, Rini
BI
, Escudier
B
, et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma
. Nat Med
. 2018 Jun 01
;24
(6
):749
–57
.68.
Cortellini
A
, Bersanelli
M
, Buti
S
, Cannita
K
, Santini
D
, Perrone
F
, et al. A multicenter study of body mass index in cancer patients treated with anti-PD-1/PD-L1 immune checkpoint inhibitors: when overweight becomes favorable
. J Immunother Cancer
. 2019 Feb 27
;7
(1
):57
. 69.
Lalani
A-KA
, Xie
W
, Flippot
R
, Steinharter
JA
, Harshman
LC
, McGregor
BA
, et al. Impact of body mass index (BMI) on treatment outcomes to immune checkpoint blockade (ICB) in metastatic renal cell carcinoma (mRCC)
. J Clin Oncol
. 2019
;37
(7_Suppl
):566
–6
. 70.
De Giorgi
U
, Procopio
G
, Giannarelli
D
, Sabbatini
R
, Bearz
A
, Buti
S
, et al. Association of systemic inflammation index and body mass index with survival in patients with renal cell cancer treated with nivolumab
. Clin Cancer Res
. 2019 Jul 1
;25
(13
):3839
–46
. 71.
Bergerot
PG
, Bergerot
CD
, Philip
EJ
, Meza
L
, Dizman
N
, Hsu
J
, et al. Targeted therapy and immunotherapy: effect of body mass index on clinical outcomes in patients diagnosed with metastatic renal cell carcinoma
. Kidney Cancer
. 2019
;3
(1
):63
–70
. 72.
Labadie
BW
, Liu
P
, Bao
R
, Crist
M
, Fernandes
R
, Ferreira
L
, et al. BMI, irAE, and gene expression signatures associate with resistance to immune-checkpoint inhibition and outcomes in renal cell carcinoma
. J Transl Med
. 2019 Nov 25
;17
(1
):386
. 73.
Ishihara
H
, Kondo
T
, Omae
K
, Takagi
T
, Iizuka
J
, Kobayashi
H
, et al. Sarcopenia and the modified glasgow prognostic score are significant predictors of survival among patients with metastatic renal cell carcinoma who are receiving first-line sunitinib treatment
. Target Oncol
. 2016 Oct
;11
(5
):605
–17
. 74.
Yip
SM
, Heng
DY
, Tang
PA
. Review of the interaction between body composition and clinical outcomes in metastatic renal cell cancer treated with targeted therapies
. J Kidney Cancer VHL
. 2016
;3
(1
):12
–22
. 75.
Cespedes Feliciano
EM
, Kroenke
CH
, Caan
BJ
. The obesity paradox in cancer: how important is muscle?
Annu Rev Nutr
. 2018 Aug 21
;38
:357
–79
. 76.
Rajandram
R
, Perumal
K
, Yap
NY
. Prognostic biomarkers in renal cell carcinoma: is there a relationship with obesity?
Transl Androl Urol
. 2019 May
;8
(Suppl 2
):S138
–S46
. 77.
Hallenborg
P
, Fjære
E
, Liaset
B
, Petersen
RK
, Murano
I
, Sonne
SB
, et al. p53 regulates expression of uncoupling protein 1 through binding and repression of PPARγ coactivator-1α
. Am J Physiol Endocrinol Metab
. 2016 Jan 15
;310
(2
):E116
–28
. 78.
Ginzac
A
, Barres
B
, Chanchou
M
, Gadéa
E
, Molnar
I
, Merlin
C
, et al. A decrease in brown adipose tissue activity is associated with weight gain during chemotherapy in early breast cancer patients
. BMC Cancer
. 2020 Feb 4
;20
(1
):96
. © 2020 S. Karger AG, Basel
2020
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.
