Simple SummaryRecently, cells of large size called PGCC (Polyploid Giant Cancer Cells) have emerged as a pillar in cancer development and progression, possibly being the “first cells” from which the cancer starts. PGCC have been studied in cancer tissues from patients and in laboratory models. They have also been found in the blood, occasionally. By applying a method able to detect rare cells in urine, we found these PGCC in the urine of patients with prostate cancer. No study has ever published this finding. Our work is preliminary but deserves to be shared with the scientific community as it opens the way for more studies targeting the role of these PGCC and their possible use as an early and non-invasive marker of prostate cancer development.AbstractProstate cancer is the third cause of cancer-related deaths in men. Its early and reliable diagnosis is still a public health issue, generating many useless prostate biopsies. Prostate cancer cells detected in urine could be the target of a powerful test but they are considered too rare. By using an approach targeting rare cells, we have analyzed urine from 45 patients with prostate cancer and 43 healthy subjects under 50 y.o. We observed a relevant number of giant cells in patients with cancer. Giant cells, named Polyploid Giant Cancer Cells (PGCC), are thought to be involved in tumorigenesis and treatment resistance. We thus performed immune-morphological studies with cancer-related markers such as α-methylacyl-CoA racemase (AMACR), prostate-specific membrane antigen (PSMA), and telomerase reverse transcriptase (TERT) to understand if the giant cells we found are PGCC or other urinary cells. We found PGCC in the urine of 22 patients, including those with early-stage prostate cancer, and one healthy subject. Although these results are preliminary, they provide, for the first time, clinical evidence that prostate cancers release PGCC into the urine. They are expected to stimulate further studies aimed at understanding the role of urinary PGCC and their possible use as a diagnostic tool and therapeutic target.