Immunosuppression via Tenascin-C

Metastasis accounts for most of the prostate cancer-related deaths, and the presence of more than two metastatic lymph nodes at radical prostatectomy and extended pelvic lymph node (PLN) dissection is an independent predictor of prostate cancer specific mortality [1], thus suggesting that PLN invasion is an important event in the history of the disease. However, despite its clinical significance, little is known about the mechanisms favoring dissemination and survival of cancer cells at sites of future metastasis. This is particularly intriguing for cancer cells invading lymph nodes, where both innate and adaptive immunity should rapidly recognize and eliminate disseminated cells. Another biological conundrum is when in the history of prostate cancer, a neoplastic cell detaches from the primary lesion and seeds the metastatic niche. Indeed, even patients affected by less aggressive prostate cancer may harbor occult lymph node metastasis, which might remain quiescent and shielded from immune surveillance for years before growing and becoming clinically relevant. Quiescence and immune evasion are characteristics of stem cells, and cancer cells with stem cell properties have been implicated in early metastatic dissemination [2]. Thus, we hypothesized that cancer stem-like cells (CSC) both at primary and metastatic sites possess mechanisms of immune evasion. We investigated this biological issue in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice that express the SV40 early genes (large and small T antigens; Tag) under the control of the probasin regulatory element selectively in the prostate epithelium. Indeed, androgen-promoted expression of Tag at puberty leads to prostate intraepithelial neoplasia (PIN; week 6-12) that invariably progresses to adenocarcinoma (week 12-18). PLN metastases from adenocarcinoma are infrequent in TRAMP mice, and in our cohort of more than 100 mice they occurred after week 17. Utilizing the sphere assay, we established long-term prostate CSC lines from unsorted prostate cells obtained from different stages of TRAMP progression [3]. CSC were endowed with self-renewal, multipotency, and tumorigenicity capacities. Transcriptome analysis showed that genes upregulated in each stage-specific prostate CSC were significantly associated with distinct clinical subgroups of prostate cancer patients, thus indicating that mouse CSC may define human prostate cancer progression signatures [3]. Although CSC obtained from PIN lesions Editorial