Although primary prostate cancer (PCa) is highly treatable, metastatic PCa remains detrimental and poses a severe therapeutic challenge. Many stresses and conventional therapies, including chemotherapy, trigger growth arrest in cells called cellular senescence, also termed as “Premature Ageing.” Premature ageing in stressed/damaged cells at early stages prevents malignant transformation (cancer initiation): however, therapy-induced senescence in cancer cells prevents cancer progression and spread. Intriguingly, under certain conditions, ageing tumour cells do not become weaker over time but, paradoxically, they help tumors to become even more aggressive and resistant to chemotherapies. This is a phenomenon that has puzzled many cancer researchers for years.  

Ilaria Guccini and Ajinkya Revandkar contemplated this unsolved problem. Their two core questions were: how come an anti-tumor process backfires and initiates metastasis which accounts for cancer-related deaths, and how can we prevent this process from getting started? 

The two researchers and their research team discovered that the metalloproteinase-1 inhibitor, TIMP-1, plays a decisive role in the distinct outcomes of ageing of cancer cells. Loss of TIMP-1 in aged cancer cells triggers reprogramming of tumor microenvironment that initiates metastasis, which doesn’t happen in the presence of intra-tumoral TIMP-1. Moreover, eliminating these premature aged TIMP-1-deficient cancer cells can block this process which vouches for the senolytic therapy for cancer treatment. Thus, this “ageing of tumor cells regime” that the tumor itself triggers, under certain circumstances, promotes metastases. Simply put: geriatric cancer cells can get going again if the TIMP-1 gene is or gets switched off.

These insights help us understand processes in tumour cell senescence in prostate cancer that were not understood to date and may influence therapy in the future.

Senescence Reprogramming by TIMP1 Deficiency Promotes Prostate Cancer Metastasis. Ilaria Guccini*, Ajinkya Revandkar*, Mariantonietta D’Ambrosio, Manuel Colucci, Emiliano Pasquini, Simone Mosole, Martina Troiani, Daniela Brina, Raheleh Sheibani-Tezerji, Angela Rita Elia, Andrea Rinaldi, Nicolò Pernigoni, Jan Hendrik Rüschoff, Susanne Dettwiler, Angelo M De Marzo, Emmanuel S Antonarakis, Costanza Borrelli, Andreas E Moor, Ramon Garcia-Escudero, Abdullah Alajati, Giuseppe Attanasio, Marco Losa, Holger Moch, Peter Wild, Gerda Egger and Andrea Alimonti. 
Cancer Cell. 2021 Jan 11;39(1):68-82.e9. doi: 10.1016/j.ccell.2020.10.012
*These authors contributed equally to this work.