In this issue of Cancer Research, Zhou and colleagues investigate the role of acute kidney injury (AKI) and AKI-associated systemic inflammation in the development of kidney cancer. They demonstrate a positive association between the formation of clear-cell renal cell carcinoma and AKI induced by ischemia-reperfusion injury in genetically modified mice. In parallel with the emergence of kidney tumors, mice with ischemic injury develop systemic inflammation associated with tissue infiltration by neutrophils and fibroblasts and upregulated expression of several inflammatory factors, with CXCL1 displaying the highest levels of upregulation. Accordingly, blockade of CXCL1-mediated signaling inhibited the emergence of kidney tumors in mice subjected to ischemic kidney injury. The study provides evidence for a new experimental approach to prevent the formation of clear-cell renal cell carcinoma and reduce kidney cancer incidence through modulation of the AKI-induced inflammatory response using inhibitors of CXC/CXCR2 axis. As the incidence of kidney cancer continues to increase, new treatment strategies for this devastating disease are urgently needed. Zhou and colleagues provide preclinical proof of concept for a new therapeutic strategy and address an unmet need for this difficult to prevent and treat cancer disease.

See related article by Zhou et al., p. 2690

Currently, an estimated 73,750 adults in the United States and 350,000 adults globally will be diagnosed with kidney cancer. Kidney cancer is the sixth most common cancer for men and eighth most common cancer for women. Kidney cancer originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. Clear-cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer in adults, responsible for approximately 75% of cases. It has been shown that 25% to 30% of affected patients have metastatic disease. Surgery remains the most effective treatment for ccRCC. However, the total recurrence rate after surgical resection remains high, estimated at 35%.

The connection between inflammation and cancer was first reported by Virchow (1). Currently, chronic inflammation is considered an independent prognostic factor for the development of several cancer types. However, to date, there is no solid evidence indicating the potential role of inflammation in the emergency of kidney cancer. Inflammation and cancer are linked by an intrinsic pathway, in which genetic events that cause cancer orchestrate the creation of an inflammatory microenvironment and an extrinsic pathway in which nonresolving chronic inflammation drives tumorigenesis (2). In early studies, it was observed that the progression of kidney cancer is associated with increased local and systemic production of various cytokines, chemokines, and inflammatory immune cells (3–5). However, whether certain inflammatory factors and specific inflammation-associated signaling pathways could directly contribute to RCC development remain to be established.

A recent study demonstrated that acute kidney injury (AKI) significantly increases the risk for papillary RCC (pRCC) development and tumor relapse in humans as confirmed by data collected from several multicenter studies (6). AKI-induced tumors originated from the clonal proliferation of renal progenitors in a classical adenoma-carcinoma sequence, leading to invasive pRCC growth and remote metastasis. To test the effects of AKI on kidney cancer development in an experimental model, the authors induced unilateral ischemia-reperfusion injury (IRI) in wild-type mice and examined their kidneys at different timepoints. They showed that hypoxia promoted the undifferentiated cell state in various stem and precursor populations by activating Notch-responsive promoters and increased expression of genes directly downstream of Notch, which drove a hypoxia-inducible factor HIF1a–to–HIF2a switch that favored transformation into cancer stem cells and supported tumor growth.

Building on this observation, Zhou and colleagues (7) used a similar approach to induce AKI in genetically modified mice with Cre-mediated deletion of Trp53 and Pten genes in Ggt1-expressing proximal tubular epithelial cells (GPPY mice). These genetic modifications resulted in the development of dysplastic lesions in kidneys, however, the rate of kidney tumor formation was low. Additional CRISPR-mediated loss of the VHL gene also did not stimulate the development of kidney tumors in GPPY mice. Because IRI-induced AKI in the kidney has been implicated as a risk factor for the development of RCC, the authors subjected the GPPY mice to IRI-inducing acute injury in one kidney. Histologic analysis of murine kidneys performed 20 to 32 weeks after IRI, revealed that IRI-induced AKI promotes the formation of ccRCC in the contralateral noninjured kidney, but not in the kidney subjected to IRI.

In parallel with the development of kidney tumors in mice with ischemic kidney injury, Zhou and colleagues observed significant increase in tissue infiltration of neutrophils and fibroblasts, which was associated with upregulated expression inflammatory factors CXCL1, CXCL13, TIMP1, and ILRα, with CXCL1 displaying the highest levels of upregulation locally and systemically. Interestingly, CXCL1 expression was predominantly associated with dysplastic epithelial cells in the ischemic reperfusion injured kidney, but not in the contralateral noninjured kidney. Expression of CXCL1 in mice without IRI was minimal, indicating the direct role of IRI-induced AKI in the stimulation of CXCL1 expression. Also, IHC staining revealed the upregulated expression of CXCR2 in stromal fibroblasts, mostly in the noninjured kidney. Because CXCR2 serves as a natural receptor for CXCL1, the authors further hypothesized that AKI-associated increase of CXCL1 in injured kidney promoted the chemokine-mediated recruitment of CXCR2-expressing fibroblasts and neutrophils. To examine the role of AKI-stimulated inflammatory response in tumor formation, Zhou and colleagues used anti-CXCR2 antibodies to block CXCL1/CXCR2 signaling. Administration of anti-CXCR2 antibodies in mice after AKI prevented recruitment of neutrophils, fibroblasts, and most importantly, reduced RCC incidence.

Overall, the study by Zhou and colleagues demonstrates the importance of AKI and AKI-stimulated systemic inflammation that involves immune, stromal, and epithelial components in the development of kidney cancer from preestablished dysplastic precursor lesions. This work also highlights the crucial role of CXCR2-mediated signaling and the CXC/CXCR2 axis in the formation of ccRCC. This finding is also supported by the fact that increased CXCR2 expression is associated with postoperative recurrence and survival of patients with nonmetastatic ccRCC (8). Chemokine-dependent signaling is important for integrin activation, cytokine production, and leukocyte recruitment. Specifically, CXCL1 is a peptide that belongs to the CXC chemokine family that specifically binds to the CXCR2 receptor and serves as a chemoattractant for CXCR2-expressing immune cells such as neutrophils, myeloid progenitors, as well as endothelial cells and fibroblasts (7, 9, 10). In addition to CXCL1, the CXCR2 receptor also binds other CXC chemokines including CXCL2, CXCL3, and CXCL5. As a member of the G protein–coupled receptor family, CXCR2 and its ligands have been increasingly implicated in processes associated with tumor progression, including angiogenesis, cancer-related inflammation, tumor proliferation, invasion, and metastasis. In addition, CXC chemokines produced by epithelial cancer cells attract the immunosuppressive CXCR2-expressing myeloid-derived suppressor cells through Hippo-Yap1–mediated signaling (10). Altogether, these facts underline the importance of CXC chemokines and the complexity of CXCR2-mediated signaling in tumor development and progression. The authors provide a strong rationale for further studies to better understand the role of AKI-triggered systemic inflammation in ccRCC susceptibility. However, the implications of their findings for kidney cancer prevention require further investigation. Therefore, future studies on the physiologic function and pathophysiologic consequences of the interaction between CXC chemokines and CXCR2 and its association with neoplastic processes may help better understand the role of inflammation in tumor development.

In conclusion, the mechanistic discoveries made by Zhou and colleagues may have significant translational implications for kidney cancer research and ccRCC prevention. Thus, inhibition of CXCR2 or its downstream signaling pathway could potentially reduce the risk of kidney cancer development in patients with AKI.

No disclosures were reported.

This work was supported by research funds from the University of Florida (Gainesville, FL).

1.
Balkwill
F
,
Mantovani
A
. 
Inflammation and cancer: back to Virchow?
Lancet
2001
;
357
:
539
45
.
2.
Mantovani
A
,
Allavena
P
,
Sica
A
,
Balkwill
F
. 
Cancer-related inflammation
.
Nature
2008
;
54
:
436
44
.
3.
Gahan
JC
,
Gosalbez
M
,
Yates
T
,
Young
EE
,
Escudero
DO
,
Chi
A
, et al
Chemokine and chemokine receptor expression in kidney tumors: molecular profiling of histological subtypes and association with metastasis
.
J Urol
2012
;
187
:
827
33
.
4.
Eruslanov
E
,
Stoffs
T
,
Kim
WJ
,
Daurkin
I
,
Gilbert
SM
,
Su
LM
, et al
Expansion of inflammatory CCR8+ myeloid cells in patients with renal and urothelial carcinomas
.
Clin Cancer Res
2013
;
19
:
1670
80
.
5.
Romo de Vivar
A
,
Finke
JH
,
Bukowski
R
. 
The role of inflammation in kidney cancer
.
Adv Exp Med Biol
2014
;
816
:
197
234
.
6.
Peired
AJ
,
Antonelli
G
,
Angelotti
ML
,
Allinovi
M
,
Guzzi
F
,
Sisti
A
, et al
Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells
.
Sci Transl Med
2020
;
12
:
eaaw6003
.
7.
Zhou
X
,
Xiao
F
,
Sugimoto
H
,
Li
B
,
McAndrews
KM
,
Kalluri
R
. 
Acute kidney injury instigates malignant renal cell carcinoma via CXCR2 in mice with inactivated Trp53 and Pten in proximal tubular kidney epithelial cells
.
Cancer Res
2021
;
81
:
2690
703
.
8.
An
H
,
Xu
L
,
Chang
Y
,
Zhu
Y
,
Yang
Y
,
Chen
L
, et al
CXC chemokine receptor 2 is associated with postoperative recurrence and survival of patients with non-metastatic clear-cell renal cell carcinoma
.
Eur J Cancer
2015
;
51
:
1953
61
.
9.
Stadtmann
A
,
Zarbock
A
. 
CXCR2: from bench to bedside
.
Front Immunol
2012
;
3
:
263
.
10.
Wang
G
,
Lu
X
,
Dey
P
,
Deng
P
,
Wu
CC
,
Jiang
S
, et al
Targeting YAP-dependent MDSC infiltration impairs tumor progression
.
Cancer Discov
2016
;
6
:
80
95
.