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Inhibition of the insulin-like growth factor-1 receptor enhances effects of Simvastatin on prostate cancer cells in co-culture with bone
Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Tandläkarutbildning.
Visa övriga samt affilieringar
2013 (Engelska)Ingår i: Cancer Microenvironment, ISSN 1875-2292, E-ISSN 1875-2284, Vol. 6, nr 3, s. 231-240Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Prostate cancer (PC) bone metastases show weak responses to conventional therapies. Bone matrix is rich in growth factors, with insulin-like growth factor-1 (IGF-1) being one of the most abundant. IGF-1 acts as a survival factor for tumor cells and we speculate that bone-derived IGF-1 counteracts effects of therapies aimed to target bone metastases and, consequently, that therapeutic effects could be enhanced if given in combination with IGF-1 receptor (IGF-1R) inhibitors. Simvastatin inhibits the mevalonate pathway and has been found to induce apoptosis of PC cells. The aims of this study were to confirm stimulating effects of bone-derived IGF-1 on PC cells and to test if IGF-1R inhibition enhances growth inhibitory effects of simvastatin on PC cells in a bone microenvironment. The PC-3 and 22Rv1 tumor cell lines showed significantly induced cell growth when co-cultured with neonatal mouse calvarial bones. The tumor cell IGF-1R was activated by calvariae-conditioned media and neutralization of bone-derived IGF-1 abolished the calvarium-induced PC-3 cell growth. Treatment of PC-3 and 22Rv1 cells with simvastatin, or the IGF-1R inhibitor NVP-AEW541, reduced tumor cell numbers and viability, and induced apoptosis. Combined simvastatin and NVP-AEW541 treatment resulted in enhanced growth inhibitory effects compared to either drug given alone. Effects of simvastatin involved down-regulation of IGF-1R in PC-3 and of constitutively active androgen receptor variants in 22Rv1 cells. In conclusion, we suggest that IGF-1 inhibition may be a way to strengthen effects of apoptosis-inducing therapies on PC bone metastases; a possibility that needs to be further tested in pre-clinical models.

Ort, förlag, år, upplaga, sidor
Springer, 2013. Vol. 6, nr 3, s. 231-240
Nyckelord [en]
Prostate cancer, Bone metastases, IGF-1R, Simvastatin, Cholesterol
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
URN: urn:nbn:se:umu:diva-65834DOI: 10.1007/s12307-013-0129-zPubMedID: 23335094OAI: oai:DiVA.org:umu-65834DiVA, id: diva2:604937
Tillgänglig från: 2013-02-12 Skapad: 2013-02-12 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
Ingår i avhandling
1. Prostate cancer and bone cell interactions: implications for metastatic growth and therapy
Öppna denna publikation i ny flik eller fönster >>Prostate cancer and bone cell interactions: implications for metastatic growth and therapy
2017 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The skeleton is the most common site of prostate cancer bone metastasis, and at present, there are no curable treatments for these patients. To further understand what stimulates tumor cell growth in the bone microenvironment and to find suitable therapies, reliable model systems are needed. For this purpose, we have developed an in vitro co-culture system that can be used to study interactions between tumor cells and murine calvarial bones. To validate the model, we measured the release of collagen fragments and monitored changes in expression levels of genes normally expressed during active bone remodeling.

One of the major reasons why prostate cancer cells colonize bone is the abundance of tumor-stimulating factors, such as insulin-like growth factors (IGFs), present in this milieu. We found that the IGF-1 receptor (IGF-1R) was one of the most highly activated receptor tyrosine kinases in tumor cell lines stimulated with bone conditioned media. Since IGF-1 is known to be a strong survival factor for tumor cells, we hypothesized, that concurrent inhibition of IGF-1R signaling can enhance the effects of apoptosis-inducing therapies, such as castration. We used our co-culture model to target human prostate cancer cell lines, PC-3 and 22Rv1, with simvastatin (an inhibitor of the mevalonate pathway and an inducer of apoptosis), in combination with anti-IGF-1R therapy. Tumor cell viability declined with either one of the therapies used alone, and the effect was even more pronounced with the combined treatment. The hypothesis was also tested in rats that had been inoculated with rat prostate cancer cells, Dunning R3327-G, into the tibial bone, and treated with either anti-IGF-1R therapy, castration, or a combination of both therapies. Immunohistochemistry was used to evaluate therapeutic effects on tumor cell proliferation and apoptosis, as well as tumor cell effects on bone remodeling. The tumor cells were found to induce an osteoblastic response, both in vivo in rats, and in vitro using the co-culture model. Interestingly, the therapeutic response differed depending on whether tumor cells were located within the bone marrow cavity or if they had leaked out into the knee joint cavity, highlighting the role of the microenvironment on metastatic growth and therapeutic response. Therapies targeting the IGF-1R have been tested in clinical trials, unfortunately with disappointing results. By immunohistochemical evaluation of bone metastases from patients with castration-resistant prostate cancer, we found a large variance in IGF-1R staining within this group of patients. Hence, we postulate that the effects of anti-IGF-1R therapies could be more beneficial in patients with high tumoral IGF-1R-activity than in IGF-1R negative cases. We also believe that side effects, such as hyperglycemia, associated with anti-IGF-1R therapy, could be reduced if this treatment is administered only to selected patients and for shorter time periods.

In a separate study, using whole-genome expression data from bone metastases obtained from prostate cancer patients, we present evidence that a high activity of osteoblasts is coupled to a high activity of osteoclast. Moreover, we found that high bone remodeling activity is inversely related to tumor cell androgen receptor (AR) activity. The results from this study may be of importance when selecting therapy for patients with bone metastatic cancer, especially when bone-targeting therapies are considered, and could aid in the search for novel therapeutic targets.

In summary, we present an in vitro model for studies of the bidirectional interplay between prostate cancer cells and the bone microenvironment. We also demonstrate the importance of IGF-1 in prostate cancer bone metastases and suggest that inhibition of IGF-1R signaling can be used to treat prostate cancer as well as to enhance effects of other treatments such as androgen deprivation therapy. Furthermore, we emphasize the possibility of molecular tumor characterization when designing treatment plans for individual patients, thereby maximizing the therapeutic effects.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå Universitet, 2017. s. 65
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1886
Nationell ämneskategori
Cancer och onkologi
Forskningsämne
onkologi
Identifikatorer
urn:nbn:se:umu:diva-131809 (URN)978-91-7601-678-7 (ISBN)
Disputation
2017-03-17, Hörsal E04, Byggnad 6A, Norrland universitetssjukhus, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2017-02-24 Skapad: 2017-02-22 Senast uppdaterad: 2018-06-09Bibliografiskt granskad

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