| 1. |
- Flaberg, E., et al.
(författare)
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High-throughput live cell imaging reveals differential inhibition of tumor cell proliferation by human fibroblasts
- 2011
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Ingår i: International Journal of Cancer. - : Wiley-Blackwell. - 0020-7136 .- 1097-0215. ; 128:12, s. 2793-2802
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Tidskriftsartikel (refereegranskat)abstract
- Increasing evidence indicates that cancer development requires changes both in the precancerous cells and in their microenvironment. To study one aspect of the microenvironmental control, we departed from Michael Stoker's observation (Stroker et al, J Cell Sci 1966;1:297-310) that normal fibroblasts can inhibit the growth of admixed cancer cells (neighbour suppression). We have developed a high-throughput microscopy and image analysis system permitting the examination of live mixed cell cultures growing on 384-well plates, at the single cell level and over time. We have tested the effect of 107 samples of low passage number (<5) primary human fibroblasts from pediatric and adult donors, on the growth of six human tumor cell lines. Three of the lines were derived from prostate carcinomas, two from lung carcinomas and one was an EBV transformed lymphoblastoid line. Labeled tumor cells were grown in the presence of unlabeled fibroblasts. The majority of the tested fibroblasts inhibited the proliferation of the tumor cells, compared to the control cultures where labeled tumor cells were co-cultured with unlabeled tumor cells. The proliferation inhibiting effect of the fibroblasts differed depending on their site of origin and the age of the donor. Inhibition required direct cell contact. Mouse 3T3 fibroblasts inhibited the growth of SV40-transformed 3T3 cells and human tumor cells, showing that the inhibitory effect could prevail across the species barrier. Our high-throughput system allows the quantitative analysis of the inhibitory effect of fibroblasts on the population level and the exploration of differences depending on the source of the normal cells.
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| 2. |
- Hilvo, Mika, et al.
(författare)
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Monounsaturated fatty acids in serum triacylglycerols are associated with response to neoadjuvant chemotherapy in breast cancer patients
- 2014
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 134:7, s. 1725-1733
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Tidskriftsartikel (refereegranskat)abstract
- Changes in cellular lipid metabolism are a common feature in most solid tumors, which occur already in early stages of the tumor progression. However, it remains unclear if the tumor-specific lipid changes can be detected at the level of systemic lipid metabolism. The objective of this study was to perform comprehensive analysis of lipids in breast cancer patient serum samples. Lipidomic profiling using an established analytical platform was performed in two cohorts of breast cancer patients receiving neoadjuvant chemotherapy. The analyses were performed for 142 patients before and after neoadjuvant chemotherapy, and the results before chemotherapy were validated in an independent cohort of 194 patients. The analyses revealed that in general the tumor characteristics are not reflected in the serum samples. However, there was an association of specific triacylglycerols (TGs) in patients' response to chemotherapy. These TGs containing mainly oleic acid (C18:1) were found in lower levels in those patients showing pathologic complete response before receiving chemotherapy. Some of these TGs were also associated with estrogen receptor status and overall or disease-free survival of the patients. The results suggest that the altered serum levels of oleic acid in breast cancer patients are associated with their response to chemotherapy.
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| 3. |
- Ludvigsson, Jonas F., 1969-, et al.
(författare)
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Reduced risk of breast, endometrial and ovarian cancer in women with celiac disease
- 2012
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Ingår i: International Journal of Cancer. - : Wiley-Blackwell. - 0020-7136 .- 1097-0215. ; 131:3, s. E244-E250
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Tidskriftsartikel (refereegranskat)abstract
- Women with celiac disease (CD) may be at decreased risk of female hormone-related cancers given the observed reduction in breast cancer seen in some cohorts. Using biopsy data from all 28 pathology departments in Sweden, we identified 17,852 women with CD who were diagnosed between 1969 and 2007. We used Cox regression model to estimate their risk of breast, endometrial and ovarian cancer and then compared them with 88,400 age- and sex-matched controls. The results indicate that individuals with CD were at a lower risk for all three outcomes: breast cancer (hazard ratio, HR = 0.85; 95% CI = 0.721.01), endometrial cancer (HR = 0.60; 95% CI =0.410.86) and ovarian cancer (HR = 0.89; 95% CI =0.591.34). This inverse relationship was strengthened when we excluded the first year of follow-up beyond CD diagnosis (breast: HR = 0.82; 95% CI =0.680.99; endometrial: HR = 0.58; 0.390.87; ovarian cancer: HR = 0.72; 0.451.15). In conclusion, CD seems to be inversely related not only to breast cancer but also to endometrial and ovarian cancer. Potential explanations include shared risk factors and early menopause.
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| 4. |
- Shaikhibrahim, Zaki, et al.
(författare)
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MED15, encoding a subunit of the mediator complex, is overexpressed at high frequency in castration-resistant prostate cancer
- 2014
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Ingår i: International Journal of Cancer. - Hoboken : Wiley-Blackwell. - 0020-7136 .- 1097-0215. ; 135:1, s. 19-26
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Tidskriftsartikel (refereegranskat)abstract
- The mediator complex is an evolutionary conserved key regulator of transcription of protein-coding genes and an integrative hub for diverse signaling pathways. In this study, we investigated whether the mediator subunit MED15 is implicated in castration-resistant prostate cancer (CRPC). MED15 expression and copy number/rearrangement status were assessed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively on 718 prostate cancer (PCa) specimens and sequenced by Sanger on a subset. Furthermore, SMAD3 phosphorylation, androgen receptor (AR) and proliferation markers were evaluated by IHC. In PCa cells, siRNA/shRNA knockdown of MED15 was followed by proliferation assays with/without dihydrotestosterone (DHT), and treatments with recombinant TGF-beta 3. Our results show that MED15 is overexpressed in 76% of distant metastatic CRPC (CRPCMET) and 70% of local-recurrent CRPC (CRPCLOC), in contrast to low frequencies in androgen-sensitive PCa, and no expression in benign prostatic tissue. Furthermore, MED15 overexpression correlates with worse clinical outcome thus defining a highly lethal phenotype. Moreover, TGF-beta signaling activation associates with MED15 overexpression in PCa tissues, and leads to increased expression of MED15 in PCa cells. MED15 knockdown effects phosphorylation and shuttling of p-SMAD3 to the nucleus as well as TGF-beta-enhanced proliferation. In PCa tissues, MED15 overexpression associates with AR overexpression/amplification and correlates with high proliferative activity. MED15 knockdown decreases both androgen-dependent and -independent proliferation in PCa cells. Taken together, these findings implicate MED15 in CRPC, and as MED15 is evolutionary conserved, it is likely to emerge as a lethal phenotype in other therapeutic-resistant diseases, and not restricted to our disease model.
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