Phosphatidylinositol 3-kinase (PI3K) pathway activation in bladder cancer

Abstract

The phosphatidylinositol 3-kinase (PI3K) pathway is a critical signal transduction pathway that regulates multiple cellular functions. Aberrant activation of this pathway has been identified in a wide range of cancers. Several pathway components including AKT, PI3K and mTOR represent potential therapeutic targets and many small molecule inhibitors are in development or early clinical trials. The complex regulation of the pathway, together with the multiple mechanisms by which it can be activated, make this a highly challenging pathway to target. For successful inhibition, detailed molecular information on individual tumours will be required and it is already clear that different tumour types show distinct combinations of alterations. Recent results have identified alterations in pathway components PIK3CA, PTEN, AKT1 and TSC1 in bladder cancer, some of which are significantly related to tumour phenotype and clinical behaviour. Co-existence of alterations to several PI3K pathway genes in some bladder tumours indicates that these proteins may have functions that are not related solely to the known canonical pathway.

Fig. 1

The class IA PI3K signalling pathway

Fig. 2

Potential pathways of urothelial tumorigenesis. Solid arrows indicate likely pathways and broken arrows indicate uncertain relationships. Low-grade papillary tumours (left) may arise via simple hyperplasia and minimal dysplasia. Invasive carcinoma (right) is believed to arise via the flat high-grade lesion CIS. A third hypothetical pathway to development of high grade papillary tumours is shown (middle). The pathway to development of T1 tumours is uncertain

Fig. 3

Mutations of PIK3CA identified in bladder cancer. a Schematic representation of the protein showing functional domains and the position of mutations identified to date. Both the adapter-binding and C2 domains interact with p85. b Comparison of PIK3CA mutations in bladder cancer and those listed in COSMIC for positions M1043, H1047, E542 and E545 excluding bladder tumour mutations modified from [23]

Fig. 4

Patterns of staining for PTEN protein in urothelial tumours. Scores are nuclear followed by cytoplasmic intensity. Normal ureter is shown as control. Staining in tumour samples was scored as 2 if it was at least as strong as the staining in controls, 1 if detectable but reduced and 0 if staining was absent. In tumour samples with scores of 1,2; 1,1; 0,1; 0,0 stromal cells with intense staining act as positive controls. All images were captured at same magnification. Reprinted from [23]

Fig. 5

Distribution of nuclear and cytoplasmic staining intensities for PTEN according to bladder tumour grade and stage. Reprinted from [23]

Fig. 6

TSC1 mutation spectrum in tuberous sclerosis complex and in bladder cancer. Amino acid positions of reported functional domains of hamartin are shown

Fig. 7

Patterns of staining for the TSC1 protein product hamartin in bladder tumours. a Normal ureter. b-j Bladder tumour tissues. b, c, d and e illustrate the range of staining intensity in positive-staining tumours. f-j show loss of hamartin expression. In i, the tumour shows loss of expression and a region of normal urothelium is present at the bottom of the image. Reprinted from [23]