Modelling aggressive prostate cancers of young men in immune-competent mice, driven by isogenic Trp53 alterations and Pten loss.

Understanding prostate cancer onset and progression in order to rationally treat this disease has been critically limited by a dire lack of relevant pre-clinical animal models. We have generated a set of genetically engineered mice that mimic human prostate cancer, initiated from the gland epithelia. We chose driver gene mutations that are specifically relevant to cancers of young men, where aggressive disease poses accentuated survival risks. An outstanding advantage of our models are their intact repertoires of immune cells. These mice provide invaluable insight into the importance of immune responses in prostate cancer and offer scope for studying treatments, including immunotherapies. Our prostate cancer models strongly support the role of tumour suppressor p53 in functioning to critically restrain the emergence of cancer pathways that drive cell cycle progression; alter metabolism and vasculature to fuel tumour growth; and mediate epithelial to mesenchymal-transition, as vital to invasion. Importantly, we also discovered that the type of p53 alteration dictates the specific immune cell profiles most significantly disrupted, in a temporal manner, with ramifications for disease progression. These new orthotopic mouse models demonstrate that each of the isogenic hotspot p53 amino acid mutations studied (R172H and R245W, the mouse equivalents of human R175H and R248W respectively), drive unique cellular changes affecting pathways of proliferation and immunity. Our findings support the hypothesis that individual p53 mutations confer their own particular oncogenic gain of function in prostate cancer.

Coexpression of MYC and BCL-2 predicts prognosis in primary gastrointestinal diffuse large B-cell lymphoma.

AIM: To investigate whether MYC and BCL-2 coexpression has prognostic significance in primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL) patients, and explore its associations with patients' clinical parameters. METHODS: Fresh and paraffin-embedded tumor tissue samples from 60 PGI-DLBCL patients who had undergone surgery at the Tianjin Medical University Cancer Institute and Hospital from January 2005 to May 2010 were obtained, and 30 lymphoid tissue samples from reactive lymph nodes of age- and sex-matched patients represented control samples. Staging and diagnostic procedures were conducted according to the Lugano staging system. All patients had been treated with three therapeutic modalities: surgery, chemotherapy, or radiotherapy. Expression of MYC and BCL-2 were detected at both protein and mRNA levels by immunohistochemistry and real-time RT-PCR. RESULTS: Positive expression levels of MYC and BCL-2 proteins were detected in 35% and 45% of patients, respectively. MYC+/BCL-2+ protein was present in 30% of patients. MYC and BCL-2 protein levels were correlated with high MYC and BCL-2 mRNA expression, respectively (both P<0.05). We found that advanced-stage disease (at IIE-IV) was associated with MYC and BCL-2 coexpression levels (P<0.05). In addition, MYC+/BCL-2+ patients had more difficulty in achieving complete remission than others (P<0.05). Presence of MYC protein expression only affected overall survival and progression-free survival (PFS) when BCL-2 protein was coexpressed. The adverse prognostic impact of MYC+/BCL-2+ protein on PFS remained significant (P<0.05) even after adjusting for age, Lugano stage, international prognostic index, and BCL-2 protein expression in a multivariable model. CONCLUSION: MYC+/BCL-2+ patients have worse chemotherapy response and poorer prognosis than patients who only express one of the two proteins, suggesting that assessment of MYC and BCL-2 expression by immunohistochemistry has clinical significance in predicting clinical outcomes of PGI-DLBCL patients.