The hallmarks of cancer: relevance to the pathogenesis of polycystic kidney disease

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a progressive inherited disorder in which renal tissue is gradually replaced with fluid-filled cysts, giving rise to chronic kidney disease (CKD) and progressive loss of renal function. ADPKD is also associated with liver ductal cysts, hypertension, chronic pain and extra-renal problems such as cerebral aneurysms. Intriguingly, improved understanding of the signalling and pathological derangements characteristic of ADPKD has revealed marked similarities to those of solid tumours, even though the gross presentation of tumours and the greater morbidity and mortality associated with tumour invasion and metastasis would initially suggest entirely different disease processes. The commonalities between ADPKD and cancer are provocative, particularly in the context of recent preclinical and clinical studies of ADPKD that have shown promise with drugs that were originally developed for cancer. The potential therapeutic benefit of such repurposing has led us to review in detail the pathological features of ADPKD through the lens of the defined, classic hallmarks of cancer. In addition, we have evaluated features typical of ADPKD, and determined whether evidence supports the presence of such features in cancer cells. This analysis, which places pathological processes in the context of defined signalling pathways and approved signalling inhibitors, highlights potential avenues for further research and therapeutic exploitation in both diseases.

Figure 1. A comparison of the pathological features of autosomal dominant polycystic kidney disease (ADPKD) and kidney cancer

Pathological features and key signalling pathways are indicated for a | ADPKD and b| kidney cancer. Numbers indicate hallmarks originally defined in cancer: (1) sustained proliferative signalling; (2) evasion of growth suppressors; (3) resistance to cell death; (4) replicative immortality; (5) induced angiogenesis; (6) deregulated cellular energetics; (7) avoiding immune destruction; (8) tumour –promoting; (9) genomic instability and mutation; and (10) invasion and metastasis; coupled with features first noted as important for ADPKD, including (11) altered ciliary signalling, and (12) changes involving calcium, cAMP and polarized fluid transport. Hallmarks of cancer are indicated in red where relevant, with bold numbers reflecting a strong association with the disease; ‘hallmarks’ of ADPKD are indicated in blue. Where a process is affected, but non-equivalently in ADPKD and cancer, it is indicated in green. Where a hallmark is not relevant or has been little studied in a given disease, it is indicated in gray. Abbreviations: AC6, adenyl cyclase type 6; V2R, vasopressin type 2 receptor; PC1/2, heterodimer of polycystins 1 and 2.

Figure 2. Signalling and drug targets relevant to the pathogenesis of ADPKD and kidney cancer

Pink ovals indicate signalling proteins that are involved in both ADPKD and renal cell carcinoma (RCC). Black arrows indicate positive regulation, whereas red lines indicate negative regulation. Dashed borders around therapeutic agents indicate drugs that are not approved but are being tested; solid borders reflect agents that are FDA-approved for metastatic RCC. Gray boxes indicate drugs that have been tested in ADPKD, whereas red boxes indicate drugs that are used or are being tested in RCC. Drugs listed for RCC include only FDA-approved agents or select agents that have been clinically tested in humans; drugs for ADPKD include those that have been tested clinically and preclinically.