Senescent tumor cells are frequently present at the invasion front-implications for improving disease control in patients with locally advanced prostate cancer

Introduction: Local tumor invasion is a critical factor for the outcome of men with prostate cancer. In particular seminal vesicle invasion (SVI) has been reported to be associated with a more unfavorable prognosis. A better understanding of the functional state of invading prostate cancer cells is crucial to develop novel therapeutic strategies for patients with locally advanced disease.Methods: The prognostic impact of local tumor progression was ascertained in over 1,000 men with prostate cancer. Prostate cancer specimens were stained by double-immunohistochemistry for the proliferation marker Ki-67 and the senescence marker p16INK4A. The migratory properties of senescent prostate cancer cells were analyzed in vitro using a wound healing assay and immunofluorescence microscopy for p16INK4A. Results: We confirm the notion that patients with SVI have a more unfavorable prognosis than patients with extraprostatic extension alone. Surprisingly, we found that the tumor invasion front frequently harbors p16INK4A positive and Ki-67 negative i.e., senescent, tumor cells. While the intraprostatic tumor periphery was a hotspot for both proliferation and expression of p16INK4A, the area of SVI showed less proliferative activity but was at the same time a hotspot of cells with increased nuclear p16INK4A expression. Senescence was associated with an accelerated migration of prostate cancer cells in vitro. Discussion/Conclusion: This proof-of-concept study shows that invading prostate cancer cells frequently show signs of cellular senescence. This finding may open new avenues for neoadjuvant and adjuvant treatment concepts in men with locally advanced prostate cancer.

Automated summary

Seminal vesicle invasion (SVI) in prostate cancer patients is associated with a worse prognosis. Tumor invasion front contains senescent tumor cells expressing p16INK4A. Senescence is associated with an increased migration of prostate cancer cells. This finding may have implications in the development of new treatment strategies for locally advanced prostate cancer.