Heterogeneity of cGMP signalling in tumour cells and the tumour microenvironment: Challenges and chances for cancer pharmacology and therapeutics

The second messenger cyclic guanosine monophosphate (cGMP) is an important regulator of human (patho-)physiology and has emerged as an attractive drug target. Currently, cGMP-elevating drugs are mainly used to treat cardiovascular diseases, but there is also increasing interest in exploring their potential for cancer prevention and therapy. In this review article, we summarise recent findings in cancer-related cGMP research, with a focus on melanoma, breast cancer, colorectal cancer, prostate cancer, glioma, and ovarian cancer. These studies indicate tremendous heterogeneity of cGMP signalling in tumour tissue. It appears that different tumour and stroma cells, and perhaps different sexes, express different cGMP generators, effectors, and degraders. Therefore, the same cGMP-elevating drug can lead to different outcomes in different tumour settings, ranging from inhibition to promotion of tumourigenesis or therapy resistance. These findings, together with recent evidence that increased cGMP signalling is associated with worse prognosis in several human cancers, challenge the traditional view that cGMP elevation generally has an anti-cancer effect. As cGMP pathways appear to be more stable in the stroma than in tumour cells, we suggest that cGMP-modulating drugs should preferentially target the tumour microenvironment. Indeed, there is evidence that phosphodiesterase 5 inhibitors like sildenafil enhance anti-tumour immunity by acting on immune cells. Moreover, many in vivo results obtained with cGMP-modulating drugs could be explained by effects on the tumour vasculature rather than on the tumour cells themselves. We therefore propose a model that incorporates the NO/cGMP signalling pathway in tumour vessels as a key target for cancer therapy. Deciphering the multifaceted roles of cGMP in cancer is not only a challenge for basic research, but also provides a chance to predict potential adverse effects of cGMP-modulating drugs in cancer patients and to develop novel anti-tumour therapies by precision targeting of the relevant cells and molecular pathways.