Sanna Kakonen

Sanna Kakonen
University of Turku | UTU · Department of Cell Biology and Anatomy

PhD, Adjunct Professor

About

74
Publications
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4,425
Citations

Publications

Publications (74)
Article
Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein specifically overexpressed on the cell membrane of prostate cancer cells. PSMA-targeted thorium-227 conjugate (PSMA-TTC, BAY 2315497) consists of a human PSMA-targeting antibody covalently linked to a 3,2-HOPO (hydroxypyridinone) chelator moiety, radiolabeled with alpha-parti...
Conference Paper
Radium-223 dichloride (Ra-223) is a targeted alpha therapy that binds to newly formed bone matrix in bone metastases and induces DNA double-strand breaks in cancer cells, osteoblasts and osteoclasts. It is used for treating men with castration-resistant prostate cancer (CRPC) and bone metastases. Enzalutamide is a second-generation androgen recepto...
Article
Full-text available
Osteolytic bone disease is a hallmark of multiple myeloma (MM) mediated by MM cell proliferation, increased osteoclast activity, and suppressed osteoblast function. The proteasome inhibitor bortezomib targets MM cells and improves bone health in MM patients. Radium-223 dichloride (radium-223), the first targeted alpha therapy approved, specifically...
Article
105 Background: Radium-223 dichloride (Ra-223) is a targeted alpha therapy that binds to newly formed bone matrix in bone metastases and induces DNA double-strand breaks in cancer cells, osteoblasts and osteoclasts. It is used for treating men with castration-resistant prostate cancer (CRPC) and bone metastases. Enzalutamide (enza) is a second-gene...
Conference Paper
Radium-223 dichloride (Ra-223) is a targeted alpha therapy that binds to newly formed bone matrix in bone metastases and induces double-stranded DNA breaks in cancer cells, osteoblasts, and osteoclasts. Ra-223 showed survival benefit in patients with bone-metastatic castration-resistant prostate cancer in a pivotal phase 3 trial. Recently, in a pha...
Article
Full-text available
Bone metastasis is a common clinical complication in several cancer types, and it causes a severe reduction in quality of life as well as lowering survival time. Bone metastases proceed through a vicious self-reinforcing cycle that can be osteolytic or osteoblastic in nature. The vicious cycle is characterized by cancer cells residing in bone relea...
Conference Paper
Radium-223 dichloride (Ra-223, Xofigo®) is a targeted alpha therapy which prolongs the survival of castration-resistant prostate cancer (CRPC) patients with symptomatic bone metastases. As a calcium-mimetic, Ra-223 selectively binds to hydroxyapatite and targets areas of high bone turnover such as bone metastases. Here, we report the effects of Ra-...
Conference Paper
Radium-223 dichloride (Ra-223, Xofigo®) is a targeted alpha therapy which prolongs the survival of castration-resistant prostate cancer (CRPC) patients with symptomatic bone metastases. As a calcium-mimetic, Ra-223 selectively binds to hydroxyapatite and targets areas of high bone turnover such as bone metastases. Here, we report the effects of Ra-...
Article
Full-text available
Aim: Bisphosphonates are used as an adjuvant treatment in breast cancer bone metastasis patients, often simultaneously with chemotherapeutic agents. Interestingly, their sequential combination has been reported to have synergistic anti-tumor effects on bone metastases in preclinical models. We studied the effects of doxorubicin (DOX) and zoledronic...
Article
Radium-223 dichloride (radium-223, Xofigo®), a targeted alpha-therapy, improves overall survival in prostate cancer patients with bone metastases. It inhibits disease progression by reducing tumor growth and tumor-induced pathological bone reaction in breast and prostate cancer mouse models. Radium-223 is actively incorporated into the bone matrix...
Article
Purpose: Radium-223 dichloride (radium-223, Xofigo?), a targeted alpha therapy, is currently used for the treatment of patients with castration-resistant prostate cancer (CRPC) with bone metastases. This study examines the mode-of-action and antitumor efficacy of radium-223 in two prostate cancer xenograft models.? Experimental Design: Mice beari...
Article
Radium-223 dichloride (radium-223), an alpha particle-emitting calcium-mimetic, improves overall survival in prostate cancer patients with symptomatic bone metastases. We have defined radium-223 mode-of-action and efficacy in two clinically relevant prostate cancer xenograft models demonstrating PSA expression and osteoblastic growth upon intratibi...
Article
Mouse models and treatments Ra-223 therapeutic effects were investigated in two clinically-relevant prostate cancer xenograft models: 1) LNCaP cell-line model (ATCC, European distributor LGC Standards) 2) LuCaP 58 patient-derived xenograft (PDX) model (licensed by Bayer from the University of Washington; abiraterone resistance demonstrated in an in...
Article
Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Breast cancer metastasis to bone results in significant morbidity and poor prognosis. Radium-223 dichloride is an alpha-emitting calcium mimetic that localizes to bone and provides targeted radiation therapy. A phase III clinical study on prostate cancer patients with bone...
Article
Full-text available
Background: Bone metastases are associated with increased morbidity and poor prognosis in breast cancer patients. Radium-223 dichloride is a calcium mimetic that localizes to bone, providing targeted therapy for skeletal metastasis. Methods: We investigated the mode of action of radium-223 dichloride using breast cancer cell, osteoclast, and ost...
Article
Full-text available
Development of bone metastases is dependent on the cancer cell-bone cell interactions in the bone microenvironment. Transforming growth factor β (TGF-β) is released from bone during osteoclastic bone resorption and induces production of osteolytic factors, such as interleukin 11 (IL-11), in breast cancer cells. IL-11 in turn increases osteolysis by...
Data
Expression of 455 miRNAs in highly metastatic MDA-MB-231(SA) and parental MDA-MB-231 cells. (XLS)
Data
Predicted miRNA seed sequence binding sites in the IL11 3' UTR. The number of mismatches and G:U wobble pairs are given in the parentheses. (XLS)
Data
Overlap between the genes over 1.5-fold downregulated in response to miR-379 in MDA-MB-231(SA) cells and gene sets in the Molecular Signatures Database (MSigDB). The most significantly overlapping gene sets are shown. (XLS)
Data
Effects of Anti-miR-204 and -379 on Smad signaling in MDA-MB-231(SA) (A) and parental MDA-MB-231 (B) cells. Smad signaling was quantified using a luciferase construct which encodes the firefly luciferase reporter gene under the control of a minimal (m)CMV promoter and tandem repeats of the Smad transcriptional response element. The luciferase repor...
Data
Genes over 1.5-fold under- or overexpressed in response to miR-379. (XLS)
Data
Genes over 1.5-fold under- or overexpressed in response to miR-204. (XLS)
Data
Overlap between the genes over 1.5-fold downregulated in response to miR-204 in MDA-MB-231(SA) cells and gene sets in the Molecular Signatures Database (MSigDB). The most significantly overlapping gene sets are shown. (XLS)
Data
Primers and probes used for quantitative RT-PCR. (XLS)
Article
Full-text available
TGF-β regulates several steps in cancer metastasis, including the establishment of bone metastatic lesions. TGF-β is released from bone during osteoclastic bone resorption and it stimulates breast cancer cells to produce osteolytic factors such as interleukin 11 (IL-11). We conducted a cell-based siRNA screen and identified heparan sulfate 6-O-sulf...
Article
Objective: Detection and localization of metastatic lesions in advanced stages of cancer is still a difficult obstacle for diagnosis and subsequent treatment decisions for an optimized cancer patient management and therapy control. Whole body molecular imaging applying positron emission tomography (PET) allows the sensitive detection of radioactive...
Article
Full-text available
Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC We report on BAY 80-6946, a highly selective and potent pan class I PI3K inhibitor currently in Phase I clinical trials. The PI3K pathway is aberrantly activated in many tumors either by growth factor receptor tyrosine kinases, or by the genetic mutation and amplificatio...
Article
Bone metastases still present an unmet need for effective treatment. One preclinical study has suggested a beneficial effect with sequential treatment of doxorubicin (DOX) and zoledronic acid (ZOL). Furthermore, bisphosphonates are used as adjuvant therapy, but controversy of their anti-tumor effects remains. We tested clinically relevant doses of...
Article
Full-text available
Sagopilone, a fully synthetic epothilone and very potent anti-tumor agent, has proved to be efficient in inhibiting bone destruction and tumor burden in a mouse model of breast cancer bone metastasis. In addition to its antiproliferative effects, this study shows direct effects of sagopilone on bone resorption and osteoclast activity. Sagopilone, a...
Article
Full-text available
The presence and localization of metastatic bone lesions is important for the staging of the disease and subsequent treatment decisions. Detecting tumor cells would have additional value over the current indirect bone scintigraphy method for detecting areas of elevated skeletal metabolic activity. d-(18)F-fluoromethyl tyrosine (d-(18)F-FMT) has rec...
Article
Metastatic bone disease caused by renal cell carcinoma (RCC) occurs frequently and becomes more and more prevalent presumably because survival times among patients with disseminated cancers are increasing. Patients with bone metastases from renal cell carcinoma suffer from severe pain, nerve compression syndromes and pathologic fractures. Very litt...
Article
Full-text available
Since bone metastatic breast cancer is an incurable disease, causing significant morbidity and mortality, an understanding of the underlying molecular mechanisms would be highly valuable. Here, we describe in vitro and in vivo evidences for the importance of serine biosynthesis in the metastasis of breast cancer to bone. We first characterized the...
Article
Nine monoclonal antibodies (Mabs) were raised against human recombinant osteocalcin fusion protein (rGST-hOC) or bovine osteocalcin (bOC) and selected to develop two-site immunoassays for human osteocalcin (hOC). The detection system was based on the time-resolved measurement of the fluorescence of europium chelates conjugated to the tracer Mabs. B...
Article
Full-text available
Bone metastases have a considerable impact on quality of life in patients with breast and other cancers. Tumors produce osteoclast-activating factors, whereas bone resorption promotes the growth of tumor cells, thus leading to a "vicious cycle" of bone metastasis. Sagopilone, a novel, fully synthetic epothilone, inhibits the growth of breast cancer...
Article
In vivo luminescent imaging technology was introduced in experimental life science research several years ago and has rapidly gained wide acceptance. By making use of this technology substantially more information can be gained from animal experiments than was previously possible. The concept of the 3Rs describes the aim to Refine, Reduce and Repla...
Article
Full-text available
Heparin-like polysaccharides possess the capacity to inhibit cancer cell proliferation, angiogenesis, heparanase-mediated cancer cell invasion, and cancer cell adhesion to vascular endothelia via adhesion receptors, such as selectins. The clinical applicability of the antitumor effect of such polysaccharides, however, is compromised by their antico...
Article
Full-text available
Osteocalcin (OC) is produced by osteoblasts during bone formation, and circulating OC has been used in clinical investigations as a marker of bone metabolism. OC is excreted into urine by glomerular filtration and can be found in urine as midmolecule fragments. We developed and evaluated three immunoassays (U-MidOC, U-LongOC, and U-TotalOC) for the...
Article
Full-text available
To examine the short- and long-term bone metabolic effects of fracture assessed by biochemical markers, we utilized a clinical fracture model-proximal tibial osteotomy-and prospectively followed 14 patients. This model of an induced fracture of a major bone gives the advantage of assessing baseline levels prior to fracture. Follow-up occurred at 6-...
Article
Full-text available
Osteoblastic bone metastases are common in prostate and breast cancer patients, but mechanisms by which tumor cells stimulate new bone formation are unclear. We identified three breast cancer cell lines that cause osteoblastic metastases in a mouse model and secrete endothelin-1. Tumor-produced endothelin-1 stimulates new bone formation in vitro an...
Article
In this study, we report the isolation and characterization of osteocalcin in human urine using mass spectrometry and N-terminal sequencing. Multiple proteolytic forms of osteocalcin were found, which consisted of 16-27 residues from the middle region of the molecule. Several fragments had residue Gly7 at the N-terminus and the most predominant was...
Article
We investigated the molecular basis for osteolytic bone metastasis by selecting human breast cancer cell line subpopulations with elevated metastatic activity and functionally validating genes that are overexpressed in these cells. These genes act cooperatively to cause osteolytic metastasis, and most of them encode secreted and cell surface protei...
Article
Osteolytic and osteoblastic metastases are often the cause of considerable morbidity in patients with advanced prostate and breast carcinoma. Breast carcinoma metastasis to bone occurs because bone provides a favorable site for aggressive behavior of metastatic cancer cells. A vicious cycle arises between cancer cells and the bone microenvironment,...
Article
Full-text available
Transforming growth factor (TGF)-beta promotes breast cancer metastasis to bone. To determine whether the osteolytic factor parathyroid hormone-related protein (PTHrP) is the primary mediator of the tumor response to TGF-beta, mice were inoculated with MDA-MB-231 breast cancer cells expressing a constitutively active TGF-beta type I receptor. Treat...
Article
Full-text available
Two different sites on vitamin K-dependent gamma-glutamyl carboxylase (VKC) are involved in enzyme-substrate interaction: the propeptide-binding site required for high-affinity substrate binding and the active site for glutamate carboxylation. Synthetic descarboxy osteocalcin (d-OC) is a low-K(m) substrate for the VKC, but unique since it possesses...
Article
A 5-year follow-up study investigated serum concentrations of total (tOC) and intact (iOC) osteocalcin in relation to calcaneal bone mineral density (BMD). The study comprised two cohorts, 75- and 80-year-olds, both resident in the city of Jyväskylä, Finland. Baseline OC and BMD were obtained for 161 men and 233 women, of whom 83 men and 189 women...
Article
TGFβ, released from bone during osteoclastic resorption, plays a central role in stimulating tumor osteolysis by inducing PTHrP in the human breast cancer cell line MDA-MB-231. However, it is unclear whether this is true for other cancer cell lines and whether factors other than PTHrP contribute to the osteolysis. Here, we report that TGFβ also reg...
Article
We examined serum total osteocalcin (TOC), carboxylated osteocalcin (COC), and their ratio (COC/TOC) by one-step two-site immunofluorescent assays in 87% (n = 792) of all home-dwelling persons of 70 years or older living in a defined area in northern Finland. Other baseline subject-related risk factors of fractures were assessed by postal questionn...
Article
Osteocalcin (OC), which is a marker of the mature osteoblasts, can also be found in posthypertrophic chondrocytes of the epiphyseal growth plate, but not in chondrocytes of the resting zone or in adult cartilage. In human osteoarthritis (OA), chondrocytes can differentiate to a hypertrophic phenotype characterized by type X collagen. The protein- a...
Article
Breast cancer metastasizes to bone more frequently than any other tumor hut the mechanisms responsible remain unclear. Parathyroid hormone-related protein (PTRrP) is an established tumor product which produces hypercalcemia by stimulating osteoclastic bone resorption. Recently, a role for PTHrP in the establishment of breast cancer metastases in bo...
Article
Full-text available
Circulating human osteocalcin (hOC) has been used as a marker of bone formation. Our aim was to validate three immunofluorometric assays (IFMAs), measuring different forms of hOC. The two-site IFMAs were based on previously characterized monoclonal antibodies. Assay 2 recognized intact hOC, assays 4 and 9 measured the NH(2)-terminal mid-fragment an...
Article
We assessed the serum concentration of gamma-carboxylated osteocalcin (OC), total OC, and full-length OC in a clinical setting of 37 patients on continuous warfarin treatment (international normalized ratio 2.0-3.8). A comparison was done with the results from 30 untreated age-matched controls. Four monoclonal antibodies, previously generated and c...
Article
We have isolated and characterized human osteocalcin (OC) fragments from pubertal urine. The fragments were isolated by immunoaffinity chromatography based on monoclonal antibody 6F9 and further purified by reverse phase chromatography. The major isolated forms, which were detectable with two-site immunofluorometric assays for serum OC, span residu...
Article
Tartrate-resistant acid phosphatase (TRAP), an enzyme expressed in bone-resorbing osteoclasts, is secreted into the circulation during bone resorption. We used six monoclonal antibodies (MAbs) to optimize direct two-site fluoroimmunoassays for determining serum TRAP concentrations. Four of the MABs, 1F1, 2H1, 4E6, and 5C1, were raised against recom...
Article
Circulating human osteocalcin (hOC) has been shown to be comprised of two main forms: the intact 1–49 form and the proteolytic N-terminal midfragment (N-mid) spanning amino acid residues 1–43 or 1–44. We used three monoclonal antibodies (MAbs) raised against hOC and bovine osteocalcin in developing a dual-label assay for the simultaneous measuremen...
Article
Osteoclasts secrete tartrate-resistant acid phosphatase (TRAP) to the circulation, where the amount of TRAP is expected to correlate with the bone resorption rate. We have developed two monoclonal antibodies, O1A and J1B, using purified human bone TRAP as antigen. The antibodies recognized different epitopes, allowing us to develop a two-site fluor...
Article
Human osteocalcin (hOC) is a 49-amino-acid peptide produced mainly by bone osteoblasts. The amount of hOC in the circulation reflects the status of bone metabolism and it is used to monitor various bone-related diseases. The aim of this study was to produce recombinant human osteocalcin (rhOC) in Escherichia coli and use it for designing new osteoc...
Article
Monoclonal antibodies (Mabs) against human osteocalcin (hOC) were made by hybridoma technology using intraperitoneally immunized mice. The immunogen was produced in a bacterial intracellular expression system, where recombinant hOC was fused to glutathione S-transferase (GST), which acted as a carrier protein. The synthetic double-stranded oligonuc...