Low endoglin vascular density and Ki67 index in Gleason score 6 tumours may identify prostate cancer patients suitable for surveillance

Josefsson, Andreas; Wikström, Pernilla; Egevad, Lars; Granfors, Torvald; Karlberg, Lars; Stattin, Pär; Bergh, Anders

doi:10.3109/00365599.2012.669791

Cited by 40 publications

(52 citation statements)

References 46 publications

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“…Irrespective of the obvious differences between a short-term rat tumor-implantation model and patients, our studies in prostate cancer patients suggest that some of the changes in TINT seen in the rat model are also present in and related to tumor aggressiveness in patients—for example, increased vascular density, accumulation of inflammatory cells, and alterations in the extracellular matrix [1, 8, 9, 13, 22]. Altered gene expression in histologically normal tumor-adjacent tissue relative to that in normal prostate tissue from men without prostate cancer has also been found in other studies [17, 23–26].…”

Section: Resultsmentioning

confidence: 99%

Characterization of a Gene Expression Signature in Normal Rat Prostate Tissue Induced by the Presence of a Tumor Elsewhere in the Organ

2015

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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.

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Section: Resultsmentioning

confidence: 99%

Characterization of a Gene Expression Signature in Normal Rat Prostate Tissue Induced by the Presence of a Tumor Elsewhere in the Organ

2015

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“…Cox regression data using a wide range of cut-offs were also constructed for the tumor Ki67-IR and pEGFR-IR data available in the database [18], [21]. For pEGFR-IR, the cut-off giving the highest significance corresponded to <3.2 and ≥3.2 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…This criteria is simply to allow for application of the marker in clinical praxis, and analysis of the previously published data for tumour pEGFR-IR and Ki67-IR scores [18], [21] indicate that these markers pass this test. For the whole dataset, the tumour pAkt-IR also has a wide range of significant cut-offs, although we did not see any prognostic value at a very high pAkt-IR, in contrast to the study of Ayala et al [9].…”

Section: Discussionmentioning

confidence: 99%

“…After boiling for 60 min in a pressure cooker, the samples were placed in TBS buffer and followed by protein block for 15 min (DAKO, Stockholm, Sweden), after which they were exposed to the primary (rabbit anti-phospho-Akt (Ser 473 ) monoclonal antibody (736E11, Cell Signaling, Danvers, MA; dilution 1/100) and the secondary system (CSA-kit which includes DAB; K1500, DAKO). Ki67 was analysed either as the number of positive stained cells crossing 11 horizontal lines across the core, or as the percentage of cells positive for this marker (reported in [21]). In the present paper, we have presented the data using the number rather than the percentage of positive stained cells.…”

Section: Methodsmentioning

confidence: 99%

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Phospho-Akt Immunoreactivity in Prostate Cancer: Relationship to Disease Severity and Outcome, Ki67 and Phosphorylated EGFR Expression

et al. 2012

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BackgroundIn the present study, we have investigated the prognostic usefulness of phosphorylated Akt immunoreactivity (pAkt-IR) in prostate cancer using a well-characterised tissue microarray from men who had undergone transurethral resection due to lower urinary tract symptoms.Methodology/Principal FindingspAkt-IR in prostate epithelial and tumour cells was assessed using a monoclonal anti-pAkt (Ser473) antibody. Immunoreactive intensity was determined for 282 (tumour) and 240 (non-mlignant tissue) cases. Tumour pAkt-IR scores correlated with Gleason score, tumour Ki67-IR (a marker of cell proliferation) and tumour phosphorylated epidermal growth factor receptor (pEGFR)-IR. For cases followed with expectancy, a high tumour pAkt-IR was associated with a poor disease-specific survival, and the prognostic information provided by this biomarker was additive to that provided by either (but not both) tumour pEFGR-IR or Ki67-IR. Upon division of the cases with respect to their Gleason scores, the prognostic value of pAkt-IR was seen for patients with Gleason score 8–10, but not for patients with Gleason score 6–7.Conclusions/SignificanceTumour pAkt-IR is associated with both disease severity and disease-specific survival. However, its clinical use as a biomarker is limited, since it does not provide prognostic information in patients with Gleason scores 6–7.

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“…Thus, while the data from the two studies are in good agreement for tumor stage 2, they diverge considerably for tumour stage 3. An additional complicating factor is the association between ErbB2-IR and the Ki67 index, given that the rate of cell proliferation is significantly higher for cases with tumour stage 3–4 than tumour stage 2 in the tissue microarray [13]. However, when ordinal regression analyses including the Ki67 index into account were undertaken, a significant interaction between AR-IR and ErbB2-IR with respect to their association with the tumour stage was found.…”

Section: Discussionmentioning

confidence: 99%

ErbB2 Receptor Immunoreactivity in Prostate Cancer: Relationship to the Androgen Receptor, Disease Severity at Diagnosis and Disease Outcome

et al. 2014

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BackgroundErbB2 is a member of the epidermal growth factor family of tyrosine kinases that is centrally involved in the pathogenesis of prostate cancer and several studies have reported that a high expression of this protein has prognostic value. In the present study, we have investigated whether tumour ErbB2 immunoreactivity (ErbB2-IR) has clinically useful prognostic value, i.e. that it provides additional prognostic information to that provided by routine clinical tests (Gleason score, tumour stage).Methodology/Principal FindingsErbB2-IR was measured in a well-characterised tissue microarray of tumour and non-malignant samples obtained at diagnosis. Additionally, mRNA levels of ErbB2-IR in the prostate were determined in the rat following manipulation of circulating androgen levels. Tumour ErbB2-IR was significantly associated with the downstream signalling molecule phosphorylated-Akt and with the cell proliferation marker Ki-67. The significant association of tumour ErbB2-IR with the Gleason score at diagnosis was lost when controlled for the association of both parameters with Ki-67. In the rat prostate, mRNA for ErbB2 was inversely associated with circulating androgen levels. There was no association between ErbB2-IR and the androgen receptor (AR)-IR in the tumours, but an interaction between the two parameters was seen with respect to their association with the tumour stage. Tumour ErbB2-IR was confirmed to be a prognostic marker for disease-specific survival, but it did not provide significant additive information to the Gleason score or to Ki-67.Conclusions/SignificanceIt is concluded that tumour ErbB2-IR is of limited clinical value as a prognostic marker to aid treatment decisions, but could be of pathophysiological importance in prostate cancer.

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Low endoglin vascular density and Ki67 index in Gleason score 6 tumours may identify prostate cancer patients suitable for surveillance

Abstract: Men with GS 6 tumours with both low Ki67 index and endoglin vascular density staining scores have a low risk of progression. Additional studies are needed to test whether these two markers can be applied to core biopsies to select patients suitable for surveillance.

Cited by 40 publications

References 46 publications

Characterization of a Gene Expression Signature in Normal Rat Prostate Tissue Induced by the Presence of a Tumor Elsewhere in the Organ

Characterization of a Gene Expression Signature in Normal Rat Prostate Tissue Induced by the Presence of a Tumor Elsewhere in the Organ

Phospho-Akt Immunoreactivity in Prostate Cancer: Relationship to Disease Severity and Outcome, Ki67 and Phosphorylated EGFR Expression

ErbB2 Receptor Immunoreactivity in Prostate Cancer: Relationship to the Androgen Receptor, Disease Severity at Diagnosis and Disease Outcome

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