EDITORIAL

Colorectal cancer prognosis and PPARd/b expression in the tumormicroenvironment

Gianluigi Mazzoccoli

Received: 9 November 2013 / Accepted: 11 November 2013

� Springer Japan 2013

The tumor microenvironment plays a key role in the ana-

tomical changes, molecular alterations and pathway

derangements that prop up the deregulation of physiolog-

ical processes leading to the onset and clinical progression

of neoplastic disease, but at the same time it could be

addressed for cancer treatment [1, 2]. In particular, the

development of appropriate vasculature is necessary to

supply nutrients and oxygen to tumor tissue: the generation

of newly formed vessels from pre-existing blood vessels is

defined as neoangiogenesis and is crucial for tumor

expansion. Tumors with a volume smaller than 0.2 cm are

composed of roughly one million cells, are nourished by

substances delivered by capillaries of the host tissue, and

exploit metabolites and oligoelements present in the

extracellular fluid. Larger tumors need the formation of

new capillary blood vessels, and neoplastic tissue induces

the existing host capillaries to bud, swing and develop

throughout the tumor. Tumor vessels are dissimilar with

respect to normal vessels and may afford a site of entrance

for metastasis, and their endothelial cells may provide

valuable targets for therapeutic approaches [3, 4]. Malig-

nancy is related to metastatic progression, which is the

principle cause of cancer-related death, and the liaison

between tumor and host tissue, as well as the interaction

between cancer cells and the niche created by the micro-

environment comprising the tumour-associated stroma,

directs the evolution of malignant neoplasms from the

beginning to metastatic spreading [5]. The process of

neoangiogenesis is controlled by growth factors, such as

vascular endothelial growth factor (VEGF), fibroblast

growth factor (FGF), and platelet-derived growth factor

(PDGF), which are produced through autocrine or para-

crine secretion by components of the tumor microenvi-

ronment and exert their effects on neighbouring cells [6].

An important interplay has been evidenced between VEGF

and transcription factors of the peroxisome proliferator–

activated receptor (PPAR) family. Specifically, PPARd/bplays a role in carcinogenesis and influences oncogenic

signalling, and modulation of this nuclear receptor by

means of inhibitory ligands has been proved to hinder

invasiveness [7]. In this perspective, the interesting find-

ings reported by J. Zhou and L. Yang and co-authors shed

new light on the role of PPARd/b in colorectal carcino-

genesis. As evidenced by this group, there was differing

expression and sub-cellular localization of this transcrip-

tion factor in the endothelial cells of vascular structures in

tumor tissue with respect to normal mucosa, and this dif-

ferent pattern seemed to influence patient survival [8]. In

particular, the increased frequency of a lower expression of

PPARd/b in the endothelial cells of the neoplastic tissue

was mostly accompanied by cytoplasmic localization, as

evidenced by immunohistochemical assay, and was asso-

ciated with increased expression of angiogenesis-related

genes, such as VEGF for vascular endothelium and D2-40

for lymphatic endothelium. It was also correlated with

better cellular differentiation, less advanced disease stage,

and more favourable overall patient survival. On the other

hand, a poorer survival was evidenced in colorectal cancer

patients characterized by low expression levels of PPARd/

b in tumor cells, suggesting that in the context of colorectal

malignant neoplasms, the same transcription factor may

This comment refers to the article available at doi:10.1007/s00535-

013-0845-7.

G. Mazzoccoli (&)

Department of Medical Sciences, Division of Internal Medicine

and Chronobiology Unit, IRCCS Scientific Institute and

Regional General Hospital ‘‘Casa Sollievo della Sofferenza’’,

Cappuccini Avenue, 71013 S.Giovanni Rotondo (FG), Italy

e-mail: g.mazzoccoli@operapadrepio.it

123

J Gastroenterol

DOI 10.1007/s00535-013-0913-z

behave as a tumor suppressor if highly expressed in tumor

tissue, or as an oncogene if highly expressed in the vas-

culature of tumor-associated stroma. These data further

corroborate the mounting evidence that the microenviron-

ment surrounding and supporting the neoplastic cells can

influence the malignancy of an emergent cancer and foster

metastatic spreading [9, 10]. The several components of the

tumor stroma play different functions, interplaying in a

complex way, and they can hard-wire a multifaceted sys-

tem that crucially determines cancer behaviour and disease

outcome, but at the same time they must be regarded as

strategic therapeutic targets.

Conflict of interest The author declare that there is no conflict of

interest.

References

1. Rajaram M, Li J, Egeblad M, Powers RS. System-wide analysis

reveals a complex network of tumor-fibroblast interactions

involved in tumorigenicity. PLoS Genet. 2013;9:e1003789.

doi:10.1371/journal.pgen.1003789.

2. Magnon C, Hall SJ, Lin J, Xue X, Gerber L, Freedland SJ,

Frenette PS. Autonomic nerve development contributes to

prostate cancer progression. Science. 2013;341:1236361. doi:10.

1126/science.1236361.

3. Polyak K, Haviv I, Campbell IG. Co-evolution of tumor cells and

their microenvironment. Trends Genet. 2009;25:30–8.

4. Joyce JA, Pollard JW. Microenvironmental regulation of metas-

tasis. Nat Rev Cancer. 2009;9:239–52.

5. Malanchi I. Tumour cells coerce host tissue to cancer spread.

BoneKEy Reports. 2013;2:371. doi:10.1038/bonekey.2013.105.

6. Li X, Kumar A, Zhang F, Lee C, Li Y, Tang Z, Arjuna P. VEGF-

independent angiogenic pathways induced by PDGF-C. Onco-

target. 2010;1:309–14.

7. Adhikary T, Brandt DT, Kaddatz K, Stockert J, Naruhn S, Mei-

ssner W, Finkernagel F, Obert J, Lieber S, Scharfe M, Jarek M,

Toth PM, Scheer F, Diederich WE, Reinartz S, Grosse R, Muller-

Brusselbach S, Muller R. Inverse PPARb/d agonists suppress

oncogenic signaling to the ANGPTL4 gene and inhibit cancer

cell invasion. Oncogene. 2013;32:5241–52. doi:10.1038/onc.

2012.549.

8. Zhou J, Yang L, Li Y, Arbman G, Chen KL, Zhou B, Yu YY,

Wang C, Mo XM, Lu Y, Zhou ZG, Sun XF. The prognostic

significance of peroxisome proliferator-activated receptor bexpression in the vascular endothelial cells of colorectal cancer.

J Gastroenterol. 2013. [Epub ahead of print] [PMID: 23821017

DOI: 10.1007/s00535-013-0845-7].

9. Oshima H, Oshima M. The inflammatory network in the gastroin-

testinal tumor microenvironment: lessons from mouse models.

J Gastroenterol. 2012;47:97–106. doi:10.1007/s00535-011-0523-6.

10. Quail DF, Joyce JA. Microenvironmental regulation of tumor

progression and metastasis. Nat Med. 2013;19(11):1423–37.

J Gastroenterol

123