Abstract
Implantation of rat prostate cancer cells into the normal rat prostate results in tumor-stimulating changes in the tumor-bearing organ, for example growth of the vasculature, an altered extracellular matrix, and influx of inflammatory cells. To investigate this response further, we compared prostate morphology and the gene expression profile of tumor-bearing normal rat prostate tissue (termed tumor-instructed/indicating normal tissue (TINT)) with that of prostate tissue from controls. Dunning rat AT-1 prostate cancer cells were injected into rat prostate and tumors were established after 10 days. As controls we used intact animals, animals injected with heat-killed AT-1 cells or cell culture medium. None of the controls showed morphological TINT-changes. A rat Illumina whole-genome expression array was used to analyze gene expression in AT-1 tumors, TINT, and in medium injected prostate tissue. We identified 423 upregulated genes and 38 downregulated genes (p<0.05, ≥2-fold change) in TINT relative to controls. Quantitative RT-PCR analysis verified key TINT-changes, and they were not detected in controls. Expression of some genes was changed in a manner similar to that in the tumor, whereas other changes were exclusive to TINT. Ontological analysis using GeneGo software showed that the TINT gene expression profile was coupled to processes such as inflammation, immune response, and wounding. Many of the genes whose expression is altered in TINT have well-established roles in tumor biology, and the present findings indicate that they may also function by adapting the surrounding tumor-bearing organ to the needs of the tumor. Even though a minor tumor cell contamination in TINT samples cannot be ruled out, our data suggest that there are tumor-induced changes in gene expression in the normal tumor-bearing organ which can probably not be explained by tumor cell contamination. It is important to validate these changes further, as they could hypothetically serve as novel diagnostic and prognostic markers of prostate cancer.
Highlights
Prostate cancer, a very common multifocal disease with highly variable behavior, is difficult to diagnose and prognosticate [1, 2]
In order to study the effect of a tumor on the surrounding normal prostate tissue (TINT), we implanted rat AT-1 prostate tumor cells into the prostates of immune-competent rats and sacrificed the animals at day 10 when the tumors were still surrounded by normal prostate tissue
As many of the genes whose expression is upregulated in TINT relative to normal prostate tissue are hypoxia-regulated—for example, Hmox, lysyl oxidase (Lox), osteopontin (Spp1), periostin (Postn_perdicted), and stroma-derived factor 1 (Cxcl12/Sdf-1), we evaluated prostate tissue hypoxia using Hypoxyprobe
Summary
A very common multifocal disease with highly variable behavior, is difficult to diagnose and prognosticate [1, 2]. The diagnosis is dependent on microscopic examination of needle biopsies of prostate tissue. The current way of overcoming this problem is to take multiple biopsies, but as biopsies only sample a minute part of the whole prostate they can miss all the tumor tissue present, or the most malignant tissue. Of the millions of men who have prostate examinations every year due to the suspicion of cancer, most have biopsies that are negative for cancer [2]. Whether this indicates that cancer is not present at all or has been missed is not generally known, but in 20% of the men examined, cancer is detected in a subsequent round of biopsies [2]. The benign tissue sampled in prostate biopsies is in some way altered by the presence and nature of tumors elsewhere in the organ, this could possibly lead to an improvement in diagnosis
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