Prostate cancer induces C/EBPβ expression in surrounding epithelial cells which relates to tumor aggressiveness and patient outcome

Abstract

Background Implantation of rat prostate cancer cells into the normal rat prostate results in tumor‐stimulating adaptations in the tumor‐bearing organ. Similar changes are seen in prostate cancer patients and they are related to outcome. One gene previously found to be upregulated in the non‐malignant part of tumor‐bearing prostate lobe in rats was the transcription factor CCAAT/enhancer‐binding protein‐β (C/EBPβ). Methods To explore this further, we examined C/EBPβ expression by quantitative RT‐PCR, immunohistochemistry, and Western blot in normal rat prostate tissue surrounding slow‐growing non‐metastatic Dunning G, rapidly growing poorly metastatic (AT‐1), and rapidly growing highly metastatic (MatLyLu) rat prostate tumors―and also by immunohistochemistry in a tissue microarray (TMA) from prostate cancer patients managed by watchful waiting. Results In rats, C/EBPβ mRNA expression was upregulated in the surrounding tumor‐bearing prostate lobe. In tumors and in the surrounding non‐malignant prostate tissue, C/EBPβ was detected by immunohistochemistry in some epithelial cells and in infiltrating macrophages. The magnitude of glandular epithelial C/EBPβ expression in the tumor‐bearing prostates was associated with tumor size, distance to the tumor, and metastatic capacity. In prostate cancer patients, high expression of C/EBPβ in glandular epithelial cells in the surrounding tumor‐bearing tissue was associated with accumulation of M1 macrophages (iNOS+) and favorable outcome. High expression of C/EBPβ in tumor epithelial cells was associated with high Gleason score, high tumor cell proliferation, metastases, and poor outcome. Conclusions This study suggest that the expression of C/EBP‐beta, a transcription factor mediating multiple biological effects, is differentially expressed both in the benign parts of the tumor‐bearing prostate and in prostate tumors, and that alterations in this may be related to patient outcome.

Metabolic readouts of tumor instructed normal tissues (TINT) identify aggressive prostate cancer subgroups for tailored therapy

“…Additionally, the hyaluronan staining score in the surrounding morphologically normal prostate tissue is associated with tumor aggressiveness and increased mortality risk (10). Similar correlations were found for microseminoprotein-beta (MSMB) and C/EBPβ expression levels found in surrounding tissue areas (11, 12). Moreover, in the stroma of tumors and in non-malignant prostate tissues, a high number of S100A9 positive inflammatory cells is associated with shorter cancer-specific survival (13), and a low stroma androgen receptor level is related to poor outcomes in PC patients (14).…”

Rat prostate tumors induce DNA synthesis in remote organs

“…Changes commonly found in the benign parts of a tumor-bearing prostate are; increased vascular growth, extracellular matrix alterations, increased inflammation, altered gene expression profiles, and a reduced response to androgen withdrawal-with some changes found already when the tumor is less than one millimeter in diameter [6][7][8][9][10][11][12][13][14][15][16] . Similar changes, coupled to tumor aggressiveness and outcome, have also been found in the benign parts of the prostate and regional lymph nodes in prostate cancer patients 7,10,13,14,[16][17][18][19][20] . We have termed this phenomenon "Tumor Instructed/Indicating Normal Tissue" or shortly TINT-changes.Tumors also signal to remote tissues, like the liver and bone marrow, to recruit proteins, inflammatory cells and mesenchymal cells 21 .…”

High‐grade tumours promote growth of other less‐malignant tumours in the same prostate

“…Implantation of Dunning rat prostate tumour cells into the prostate of syngeneic and fully immunocompetent rats alters global gene expression profiles and tissue morphology in the non‐malignant prostate tissue. The nature and magnitude of these changes, named TINT changes (tumour instructed normal tissue), are related to tumour size, distance to the tumour, tumour growth rate, and metastatic capacity [3–10]. For example, the growth of highly metastatic MLL tumours results in increased vascular density and accumulation of tumour‐promoting macrophages in the benign parts of the organ, and promotes a gene expression profile corresponding to immunosuppression [4,8,10].…”