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Rudolfsson, Stina H.
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Publications (10 of 22) Show all publications
Halin Bergström, S., Rudolfsson, S. H. & Bergh, A. (2016). Rat Prostate Tumor Cells Progress in the Bone Microenvironment to a Highly Aggressive Phenotype. Neoplasia, 18(3), 152-161
Open this publication in new window or tab >>Rat Prostate Tumor Cells Progress in the Bone Microenvironment to a Highly Aggressive Phenotype
2016 (English)In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 18, no 3, p. 152-161Article in journal (Refereed) Published
Abstract [en]

Prostate cancer generally metastasizes to bone, and most patients have tumor cells in their bone marrow already at diagnosis. Tumor cells at the metastatic site may therefore progress in parallel with those in the primary tumor. Androgen deprivation therapy is often the first-line treatment for clinically detectable prostate cancer bone metastases. Although the treatment is effective, most metastases progress to a castration-resistant and lethal state. To examine metastatic progression in the bone microenvironment, we implanted androgen-sensitive, androgen receptor-positive, and relatively slow-growing Dunning G (G) rat prostate tumor cells into the tibial bone marrow of fully immune-competent Copenhagen rats. We show that tumor establishment in the bone marrow was reduced compared with the prostate, and whereas androgen deprivation did not affect tumor establishment or growth in the bone, this was markedly reduced in the prostate. Moreover, we found that, with time, G tumor cells in the bone microenvironment progress to a more aggressive phenotype with increased growth rate, reduced androgen sensitivity, and increased metastatic capacity. Tumor cells in the bone marrow encounter lower androgen levels and a higher degree of hypoxia than at the primary site, which may cause high selective pressures and eventually contribute to the development of a new and highly aggressive tumor cell phenotype. It is therefore important to specifically study progression in bone metastases. This tumor model could be used to increase our understanding of how tumor cells adapt in the bone microenvironment and may subsequently improve therapy strategies for prostate metastases in bone.

Place, publisher, year, edition, pages
Elsevier, 2016
National Category
Medical Bioscience
Identifiers
urn:nbn:se:umu:diva-119077 (URN)10.1016/j.neo.2016.01.007 (DOI)000372308400003 ()
Available from: 2016-04-15 Created: 2016-04-11 Last updated: 2018-06-07Bibliographically approved
Hammarsten, P., Winther, J., Rudolfsson, S. H., Häggström, J., Karalija, A., Egevad, L., . . . Fowler, C. (2014). ErbB2 Receptor Immunoreactivity in Prostate Cancer: Relationship to the Androgen Receptor, Disease Severity at Diagnosis and Disease Outcome. PLoS ONE, 9(9), Article ID e105063.
Open this publication in new window or tab >>ErbB2 Receptor Immunoreactivity in Prostate Cancer: Relationship to the Androgen Receptor, Disease Severity at Diagnosis and Disease Outcome
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, article id e105063Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: ErbB2 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 FINDINGS: ErbB2-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/SIGNIFICANCE: It 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.

Place, publisher, year, edition, pages
Public Library Science, 2014
National Category
Immunology in the medical area Other Basic Medicine
Identifiers
urn:nbn:se:umu:diva-93295 (URN)10.1371/journal.pone.0105063 (DOI)000341774300001 ()25215939 (PubMedID)
Available from: 2014-09-16 Created: 2014-09-16 Last updated: 2018-06-07Bibliographically approved
Rudolfsson, S. (2013). Att hämma tumörtillväxt (1ed.). In: Mattias Grundström Mitz och Lena Åminne (Ed.), Cancerforskning på nya vägar: en bok från Forskningens dag 2013, Medicinska fakulteten vid Umeå universitet (pp. 69-76). Umeå: Umeå universitet
Open this publication in new window or tab >>Att hämma tumörtillväxt
2013 (Swedish)In: Cancerforskning på nya vägar: en bok från Forskningens dag 2013, Medicinska fakulteten vid Umeå universitet / [ed] Mattias Grundström Mitz och Lena Åminne, Umeå: Umeå universitet , 2013, 1, p. 69-76Chapter in book (Other (popular science, discussion, etc.))
Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2013 Edition: 1
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-87786 (URN)978-91-7459-805-6 (ISBN)
Available from: 2014-04-09 Created: 2014-04-09 Last updated: 2018-06-08Bibliographically approved
Jernberg, E., Thysell, E., Bovinder Ylitalo, E., Rudolfsson, S., Crnalic, S., Widmark, A., . . . Wikström, P. (2013). Characterization of prostate cancer bone metastases according to expression levels of steroidogenic enzymes and androgen receptor splice variants. PLoS ONE, 8(11), e77407
Open this publication in new window or tab >>Characterization of prostate cancer bone metastases according to expression levels of steroidogenic enzymes and androgen receptor splice variants
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 11, p. e77407-Article in journal (Refereed) Published
Abstract [en]

Background: Intra-tumoral steroidogenesis and constitutive androgen receptor (AR) activity have been associated withcastration-resistant prostate cancer (CRPC). This study aimed to examine if CRPC bone metastases expressed higher levels ofsteroid-converting enzymes than untreated bone metastases. Steroidogenic enzyme levels were also analyzed in relation toexpression of constitutively active AR variants (AR-Vs) and to clinical and pathological variables.

Methodology/Principal Findings: Untreated, hormone-naıve (HN, n = 9) and CRPC bone metastases samples (n = 45) wereobtained from 54 patients at metastasis surgery. Non-malignant and malignant prostate samples were acquired from 13prostatectomy specimens. Transcript and protein levels were analyzed by real-time RT-PCR, immunohistochemistry andimmunoblotting. No differences in steroidogenic enzyme levels were detected between CRPC and HN bone metastases.Significantly higher levels of SRD5A1, AKR1C2, AKR1C3, and HSD17B10 mRNA were however found in bone metastases thanin non-malignant and/or malignant prostate tissue, while the CYP11A1, CYP17A1, HSD3B2, SRD5A2, and HSD17B6 mRNAlevels in metastases were significantly lower. A sub-group of metastases expressed very high levels of AKR1C3, which wasnot due to gene amplification as examined by copy number variation assay. No association was found between AKR1C3expression and nuclear AR staining, tumor cell proliferation or patient outcome after metastases surgery. With only oneexception, high AR-V protein levels were found in bone metastases with low AKR1C3 levels, while metastases with highAKR1C3 levels primarily contained low AR-V levels, indicating distinct mechanisms behind castration-resistance in individualbone metastases.

Conclusions/Significance: Induced capacity of converting adrenal-gland derived steroids into more potent androgens wasindicated in a sub-group of PC bone metastases. This was not associated with CRPC but merely with the advanced stage ofmetastasis. Sub-groups of bone metastases could be identified according to their expression levels of AKR1C3 and AR-Vs,which might be of relevance for patient response to 2nd line androgen-deprivation therapy.

Place, publisher, year, edition, pages
Public Library of Science, 2013
Keywords
prostate cancer, bone metastases, androgen receptor splice variants, steroidogenic enzymes
National Category
Basic Medicine Cancer and Oncology
Research subject
molecular medicine (medical sciences)
Identifiers
urn:nbn:se:umu:diva-83840 (URN)10.1371/journal.pone.0077407 (DOI)000327162900006 ()24244276 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer Society
Available from: 2013-12-10 Created: 2013-12-10 Last updated: 2018-06-08Bibliographically approved
Johansson, A., Rudolfsson, S. H., Kilter, S. & Bergh, A. (2011). Targeting castration-induced tumour hypoxia enhances the acute effects of castration therapy in a rat prostate cancer model. BJU International, 107(11), 1818-1824
Open this publication in new window or tab >>Targeting castration-induced tumour hypoxia enhances the acute effects of castration therapy in a rat prostate cancer model
2011 (English)In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 107, no 11, p. 1818-1824Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: •  To explore the effects of castration therapy, the standard treatment for advanced prostate cancer, in relation to tumour hypoxia and to elicit its importance for the short- and long-term therapeutic response.

MATERIAL AND METHODS: •  We used the androgen-sensitive rat Dunning H prostate tumour model that transiently responds to castration treatment followed by a subsequent relapse, much like the scenario in human patients. •  Tumour tissues were analysed using stereological methods in intact, 1 and 7 days after castration therapy.

RESULTS: •  Hypoxia was transiently up-regulated after castration therapy and correlated with the induction of tumour cell apoptosis. •  When castration therapy was combined with tirapazamine (TPZ), a drug that targets hypoxic cells and the vasculature, the effects on tumour cell apoptosis and tumour volume were enhanced in comparison to either castration or TPZ alone.

CONCLUSION: •  The present study suggests that castration-induced tumour hypoxia is a novel target for therapy.

Keywords
hypoxia;castration;tirapazamine;prostate;Dunning H
National Category
Cell and Molecular Biology
Research subject
Pathology
Identifiers
urn:nbn:se:umu:diva-40758 (URN)10.1111/j.1464-410X.2010.09690.x (DOI)20860653 (PubMedID)
Available from: 2011-03-09 Created: 2011-03-09 Last updated: 2018-06-08Bibliographically approved
Hammarsten, P., Karalija, A., Josefsson, A., Rudolfsson, S. H., Wikström, P., Egevad, L., . . . Bergh, A. (2010). Low levels of phosphorylated epidermal growth factor receptor in nonmalignant and malignant prostate tissue predict favorable outcome in prostate cancer patients.. Clinical Cancer Research, 16(4), 1245-1255
Open this publication in new window or tab >>Low levels of phosphorylated epidermal growth factor receptor in nonmalignant and malignant prostate tissue predict favorable outcome in prostate cancer patients.
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2010 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 16, no 4, p. 1245-1255Article in journal (Refereed) Published
Abstract [en]

PURPOSE: To explore if the expression of phosphorylated epidermal growth factor receptor (pEGFR) in nonmalignant and malignant prostate tissue is a potential prognostic marker for outcome in prostate cancer patients. EXPERIMENTAL DESIGN: We used formalin-fixed tissues obtained through the transurethral resection of the prostate from 259 patients diagnosed with prostate cancer after the transurethral resection of the prostate, and patients were then followed with watchful waiting. Tissue microarrays of nonmalignant and malignant prostate tissue were stained with an antibody against pEGFR. The staining pattern was scored and related to clinicopathologic parameters and to outcome. RESULTS: Low phosphorylation of EGFR in prostate epithelial cells, both in the tumor and surprisingly also in the surrounding nonmalignant tissue, was associated with significantly longer cancer-specific survival in prostate cancer patients. This association remained significant when Gleason score and local tumor stage were added together with pEGFR to a Cox regression model. Tumor epithelial pEGFR immunoreactivity was significantly correlated to tumor cell proliferation, tumor vascular density, and nonmalignant epithelial pEGFR immunoreactivity. Patients with metastases had significantly higher immunoreactivity for tumor and nonmalignant epithelial pEGFR compared with patients without metastases. CONCLUSIONS: Low pEGFR immunoreactivity is associated with the favorable prognosis in prostate cancer patients and may provide information about which patients with Gleason score 6 and 7 tumors that will survive their disease even without treatment. Changes in the nonmalignant tissue adjacent to prostate tumors give prognostic information.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-32701 (URN)10.1158/1078-0432.CCR-09-0103 (DOI)000278545200018 ()20145160 (PubMedID)
Available from: 2010-03-22 Created: 2010-03-22 Last updated: 2018-06-08Bibliographically approved
Johansson, A., Rudolfsson, S., Hammarsten, P., Halin, S., Pietras, K., Jones, J., . . . Bergh, A. (2010). Mast cells are novel independent prognostic markers in prostate cancer and represent a target for therapy. American Journal of Pathology, 177(2), 1031-1041
Open this publication in new window or tab >>Mast cells are novel independent prognostic markers in prostate cancer and represent a target for therapy
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2010 (English)In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 177, no 2, p. 1031-1041Article in journal (Refereed) Published
Abstract [en]

Mast cells affect growth in various human tumors, but their role in prostate cancer (PC) is unclear. Here, we identify mast cells as independent prognostic markers in PC using a large cohort of untreated PC patients with a long follow-up. By analyzing mast cells in different tissue compartments, our data indicate that intratumoral and peritumoral mast cells have anti- opposed to protumor properties. Intratumoral mast cells negatively regulate angiogenesis and tumor growth, whereas peritumoral mast cells stimulate the expansion of human prostate tumors. We also observed mast cell recruitment particularly to the peritumoral compartment in men during the formation of castrate-resistant prostate tumors. In our ortothopic rat model, mast cells accumulated in the peritumoral tissue where they enhanced angiogenesis and tumor growth. In line with this, prostate mast cells expressed high levels of the angiogenic factor FGF-2. Similar to the situation in men, mast cells infiltrated rat prostate tumors that relapsed after initially effective castration treatment, concurrent with a second wave of angiogenesis and an up-regulation of FGF-2. We conclude that mast cells are novel independent prognostic markers in PC and affect tumor progression in animals and patients. In addition, peritumoral mast cells provide FGF-2 to the tumor micro environment, which may contribute to their stimulating effect on angiogenesis.

National Category
Pathobiology
Research subject
Pathology
Identifiers
urn:nbn:se:umu:diva-40761 (URN)10.2353/ajpath.2010.100070 (DOI)000280894600051 ()20616342 (PubMedID)
Available from: 2011-03-09 Created: 2011-03-09 Last updated: 2018-06-08Bibliographically approved
Halin, S., Häggström Rudolfsson, S., Doll, J. A., Crawford, S. E., Wikström, P. & Bergh, A. (2010). Pigment epithelium-derived factor stimulates tumor macrophage recruitment and is downregulated by the prostate tumor microenvironment. Neoplasia, 12(4), 336-345
Open this publication in new window or tab >>Pigment epithelium-derived factor stimulates tumor macrophage recruitment and is downregulated by the prostate tumor microenvironment
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2010 (English)In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 12, no 4, p. 336-345Article in journal (Refereed) Published
Abstract [en]

Pigment epithelium-derived factor (PEDF) is a potent inhibitor of angiogenesis but whether it has additional effects on the tumor microenvironment is largely unexplored. We show that overexpression of PEDF in orthotopic MatLyLu rat prostate tumors increased tumor macrophage recruitment. The fraction of macrophages expressing inducible nitric oxide synthase, a marker of cytotoxic M1 macrophages, was increased, suggesting that PEDF could enhance antitumor immunity. In addition, PEDF overexpression reduced vascular growth both in the tumor and in the surrounding normal tissue, slowed tumor growth, and decreased lymph node metastasis. Contrary, extratumoral lymphangiogenesis was increased. PEDF expression is, for reasons unknown, often decreased or lost during prostate tumor progression. When AT-1 rat prostate tumor cells, expressing high levels of PEDF messenger RNA (mRNA) and protein, were injected into the prostate, PEDF is markedly downregulated, suggesting that factors in the microenvironment suppressed its expression. One such factor could be macrophage-derived tumor necrosis factor alpha (TNFα). A fraction of the accumulating macrophages expressed TNFα, and TNFα treatment downregulated the expression of PEDF protein and mRNA in prostate AT-1 tumor cells in vitro and in the rat ventral prostate in vivo. PEDF apparently has multiple effects in prostate tumors: it suppresses angiogenesis and metastasis, but it also causes macrophage accumulation. Accumulating macrophages may inhibit tumor growth, but they may also suppress PEDF and enhance lymph angiogenesis and, in this way, eventually enhance tumor growth.

Place, publisher, year, edition, pages
Neoplasia press, 2010
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-33268 (URN)10.1593/neo.92046 (DOI)000277646000005 ()20360944 (PubMedID)
Available from: 2010-04-20 Created: 2010-04-20 Last updated: 2018-06-08Bibliographically approved
Halin, S., Häggström Rudolfsson, S., Van Rooijen, N. & Bergh, A. (2009). Extratumoral macrophages promote tumor and vascular growth in an orthotopic rat prostate tumor model.. Neoplasia, 11(2), 177-186
Open this publication in new window or tab >>Extratumoral macrophages promote tumor and vascular growth in an orthotopic rat prostate tumor model.
2009 (English)In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 11, no 2, p. 177-186Article in journal (Refereed) Published
Abstract [en]

Tumor-associated macrophages are involved in angiogenesis and tumor progression, but their role and specific site of action in prostate cancer remain unknown. To explore this, Dunning R-3327 AT-1 rat prostate tumor cells were injected into the prostate of syngenic and immunocompetent Copenhagen rats and analyzed at different time points for vascular proliferation and macrophage density. Endothelial proliferation increased with tumor size both in the tumor and importantly also in the extratumoral normal prostate tissue. Macrophages accumulated in the tumor and in the extratumoral normal prostate tissue and were most abundant in the invasive zone. Moreover, only extratumoral macrophages showed strong positive associations with tumor size and extratumoral vascular proliferation. Treatment with clodronate-encapsulated liposomes reduced the monocyte/macrophage infiltration and resulted in a significant inhibition of tumor growth. This was accompanied by a suppressed proliferation in microvessels and in the extratumoral prostate tissue also in arterioles and venules. The AT-1 tumors produced, as examined by RT(2) Profiler PCR arrays, numerous factors promoting monocyte recruitment, angiogenesis, and tissue remodeling. Several, namely, chemokine (C-C) ligand 2, fibroblast growth factor 2, matrix metalloproteinase 9, interleukin 1beta, interferon gamma, and transforming growth factor beta, were highly upregulated by the tumor in vivo compared with tumor cells in vitro, suggesting macrophages as a plausible source. In conclusion, we here show the importance of extratumoral monocytes/macrophages for prostate tumor growth, angiogenesis, and extratumoral arteriogenesis. Our findings identify tumor-associated macrophages and several chemotactic and angiogenic factors as potential targets for prostate cancer therapy.

Keywords
Animals, Biological Markers/analysis, Carbonic Anhydrases/analysis, Cell Hypoxia, Epithelial Cells/chemistry, Gene Expression/drug effects, Hypoxia-Inducible Factor 1; alpha Subunit/genetics/*metabolism, Male, Neovascularization; Physiologic, Nitroimidazoles/analysis, Orchiectomy, Prostate/blood supply/*growth & development/metabolism, RNA; Messenger/analysis, Rats, Rats; Sprague-Dawley, Receptor; Epidermal Growth Factor/drug effects/physiology, Signal Transduction/drug effects, Testosterone/*pharmacology, Vascular Endothelial Growth Factor A/analysis/genetics
Identifiers
urn:nbn:se:umu:diva-26492 (URN)19177202 (PubMedID)
Available from: 2009-10-12 Created: 2009-10-12 Last updated: 2018-06-08Bibliographically approved
Rudolfsson, S. H. & Bergh, A. (2009). Hypoxia drives prostate tumour progression and impairs the effectiveness of therapy, but can also promote cell death and serve as a therapeutic target.. Expert opinion on therapeutic targets, 13(2), 219-225
Open this publication in new window or tab >>Hypoxia drives prostate tumour progression and impairs the effectiveness of therapy, but can also promote cell death and serve as a therapeutic target.
2009 (English)In: Expert opinion on therapeutic targets, ISSN 1744-7631, Vol. 13, no 2, p. 219-225Article in journal (Refereed) Published
Abstract [en]

Hypoxia is common in prostate tumours, promoting tumour progression and impairing treatment responses. Hypoxia stimulates angiogenesis but blood vessels formed in tumours are functionally abnormal so the tissue remains hypoxic. Castration treatment is the standard therapy for advanced prostate cancer. In non-malignant prostate tissue castration-induced epithelial cell death is in part mediated by vascular insult and acute hypoxia, but in prostate tumours the cell death response is less prominent and the tumours will eventually relapse. The effect of androgen ablation therapy should therefore be enhanced by additional targeting of the vasculature and hypoxic tumour cells. However if castration fails to kill a sufficiently large number of cells it could by inducing hypoxia make the situation worse. Androgen ablation treatment, may, after the initial vascular insult, result in temporary vascular normalisation and transiently increased tissue oxygen levels. During this time window, which needs to be better defined, the efficacy of cytotoxic drug and radiation treatments are probably enhanced. In order to allow development of more effective treatment strategies for advanced prostate cancer we need to understand the role of hypoxia in prostate cancer progression and treatment responses. With this knowledge we can properly tailor and time additional treatments with androgen ablation.

Identifiers
urn:nbn:se:umu:diva-26493 (URN)10.1517/14728220802626249 (DOI)19236239 (PubMedID)
Available from: 2009-10-12 Created: 2009-10-12 Last updated: 2018-06-08
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