Seminars in Cancer Biology 23 (2013) 1–2

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Seminars in Cancer Biology

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Editorial

Kidney cancer

To date renal cell carcinoma (RCC) accounts for about 2% of all activated when oxygen levels reach a critical level, and the HIF
cancers, rendering it an intermediate position between the rare transcription factors then induce the expression of genes regu-
and common. Globally the incidence is increasing however and lating for example glucose transport, glycolysis and angiogenesis.
the frequency varies in different parts of the world, with the high- Since hypoxia almost invariably arises in solid tumors when tumor
est incidence in North America and Scandinavia [1]. RCC emanates growth surpasses the angiogenic support, the elucidation of this
from the renal tubules and most investigators believe that the char- pathway has not only been of vital importance for the understand-
acteristics of the various forms of RCC mirror the histological and ing of CCRCC but now also represents a universal theme that has
cellular diversity of the renal nephron. to be taken into account in all fields cancer research. Shen and
An interesting feature of this malignancy is the emerging evi- Kaelin summarize in their review the current understanding of
dence that most RCC:s pathobiologically constitute examples of the VHL/HIF axis. The VHL syndrome is a rare autosomally inher-
perturbations of central themes of cellular metabolism. Probably ited neoplastic syndrome caused by germline mutation of the VHL
the most pertinent example of which is clear cell RCC (CCRCC), gene. The VHL patients have a high propensity for developing a
accounting for some 80% of all RCC. It has been shown that the initi- set of benign or malignant tumors, of which CCRCC represents
ating event in the absolute majority of these neoplasms centers on the major clinical challenge. In their review, Stephane Richard
the hypoxia sensing machinery of the tubular cells, due to defective and co-workers not only describe these different malignancies,
function of the von Hippel–Lindau (VHL) protein. Born in the town but also the clinical practice that have developed during recent
where these words are written, Arvid Lindau was later to become years to curb the potentially life-threatening consequences of
professor of pathology at Lund University. For his doctoral thesis, them.
Lindau investigated hemangiomata of the central nervous system Not many malignancies have such a distinct starting point for
and connected these to a similar lesion of the retina described by malignification as loss of VHL, and this may be why CCRCC is a
the german pathologist Eugen von Hippel. relatively homogenous cancer manifestation. However, CCRCC is
To dedicate this issue of Seminars in Cancer Biology to renal cell also sadly refractory to cytostatic treatment and radiation alike and
carcinoma seems timely for several reasons. A distinct and patho- metastazized disease is almost invariably deadly. Primary surgery
genetically sound classification of renal neoplasia was conceived as has almost been the only therapeutic option associated with pro-
late as 1997 [2]. Although a great achievement, this made much of longed survival. However 40% of patients treated with surgery of
the earlier work on RCC immediately obsolete, of course also setting curative intention later present with metastases and 30% of RCC
the stage for the progress that we have witnessed during the last patients present with metastatic disease, most often leading to pal-
decade. In an introductory article, Professor Holger Moch presents liative care without intervention [4]. The only options apart from
an outline of the molecular-genetical and phenotypical features of surgery has been interferon-␣ or interleukin-2 treatment offering
the main RCC forms. What is evident from this overview is the fact prolonged survival for a depressingly low number of patients. This
that characterization of RCC forms is still a work in progress, with grim backdrop has changed dramatically during the last 5 years
a host of new entities recently defined. Major advancement in the or so due to a surge of novel treatment modalities, mainly tar-
understanding of the genetic and epigenetic landscape of tumors geting the rich, almost excessive tumor vasculature of CCRCC. If
is currently taking place, thanks to the break-through of genome- not a cornucopia of agents, at least a rich bouquet of treatments
scale analyses techniques. With regard to renal malignancies much are now available to prolong the life of patients suffering from
focus has been on understanding the role of VHL in CCRCC, but RCC, summarized in the review by Fisher, Gore and Larkin. Fol-
recent findings also highlight the role of other genes, such as the lowing the initial furore, anti-angiogenetic treatment has had a
chromatin modifiers PBRM-1 and SETD2 [3]. In the review by Pro- hard time to find its place in oncology, but CCRCC has become
fessor Eamonn Maher the current understanding of the genetic an important instance of successful treatment using this princi-
landscape in the different sporadic and hereditary renal malignan- ple and the achievements have energized research efforts directed
cies is presented. at RCC. As promising as these treatment regimens may be, it is of
Over the last twenty years or so it has become clear that much course important to bear in mind that no new treatments are cura-
of the tumor suppressing function of pVHL is associated with its tive and to many patients they offer a relatively modest addition
function as a substrate recognition module of a ubiquitin ligase, of life, highlighting the total lack of predictive markers for these
that in an oxygen-dependent manner targets the HIF-alpha tran- patients and very limited knowledge concerning tailoring of treat-
scription factors for degradation. In normal cells this system gets ment.

1044-579X/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.semcancer.2012.05.006
2 Editorial / Seminars in Cancer Biology 23 (2013) 1–2

Despite the fact that renal malignancies consist of a rather dis- damaged kidneys since a perturbed regenerative process might
parate group of malignancies, most likely developing from different at least in some instances represent a likely disease causing pro-
cell types of the kidney, each with a different course and clin- cess.
ical challenges, the genes associated with the different types of
kidney cancer share a common theme in that they are involved References
in regulating cellular response to cellular stress, such as oxygen
or nutrient deprivation. The perturbation of key metabolic path- [1] Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of eigh-
ways in cancer has during recent years enabled the evolution of teen major cancers in 1985. International Journal of Cancer 1993;54(4):
594–606.
one of the most exciting avenues for development novel treat- [2] Kovacs G, Akhtar M, Beckwith BJ, Bugert P, Cooper CS, Delahunt B, et al.
ment modalities. As pointed out in the review by Linehan and The Heidelberg classification of renal cell tumours. Journal of Pathology
Ricketts, at least 12 genes associated with cellular response to 1997;183(2):131–3.
[3] Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P, et al. Exome sequenc-
stress have been implicated in the different types of kidney can-
ing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal
cer. A deepened understanding of the functional consequences carcinoma. Nature 2011;469(7331):539–42.
of these molecular changes could potentially not only pave the [4] Cohen HT, McGovern FJ. Renal-cell carcinoma. New England Journal of Medicine
way for more efficient treatment modalities of renal cancer, but 2005;353(23):2477–90.

may also provide the framework for a better understanding of

the roles played by these processes in tumorigenesis in gen- Martin E. Johansson ∗
eral. Håkan Axelson
While the genetic aspects of renal cancer is currently is being Center for Molecular Pathology, Department of
elucidated, the cellular origin of the different types of kidney Laboratory Medicine, Lund University, Skåne
cancer still to a large extent remains unclear. Historically, this University Hospital Malmö, SE-205 02 Malmö,
has been based on the histological assessments of expression of Sweden
marker proteins associated with a specific cell types of normal
∗ Corresponding author. Tel.: +46 40 337387;
kidney, but given the notorious infidelity and plasticity of tumor
cells in combination with the large number of cell types that fax: +46 40 337322.
constitute a kidney the picture is far from clear. We therefore E-mail address: martin.johansson@med.lu.se
also discuss kidney cancer in light of the regenerative capacity of (M.E. Johansson)