Publications by authors named "Vihinen P"

51 Publications

Increased gene expression levels of collagen receptor integrins are associated with decreased survival parameters in patients with advanced melanoma.

Melanoma Res 2007 Aug;17(4):215-23

Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland.

Expression of collagen receptor integrins alpha1beta1 and alpha2beta1 has been associated with progression and metastatic potential of malignant melanoma. Integrin alpha2beta1 was originally characterized as a melanoma progression antigen. We have used real-time quantitative PCR to study the mRNA expression levels of three collagen receptor integrin chains, that is alpha1, alpha2 and alpha11 in metastases from 26 patients with melanoma. Interestingly, we find that survival after initiation of chemoimmunotherapy was significantly decreased in all patients whose tumours expressed high mRNA levels of alpha1 integrin, alpha2 integrin or alpha11 integrin when compared with lower tumour expression levels (P<0.05, log rank test). Moreover, those patients with high mRNA levels of all studied integrins had a significantly shorter survival from the appearance of the first metastasis than the patients with low levels of integrins (P<0.05). Furthermore, a high mRNA expression level of integrin alpha2 was found to be associated with poorer overall survival. High alpha2 mRNA levels (n=6) were associated with median survival of 35 months and low alpha2 mRNA levels (n=20), with median survival of 53 months (P=0.033). We conclude that collagen receptor integrins are important in the progression and prognosis of metastatic melanoma, and their measurements might be used as predictive markers when assessing disease progression.
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http://dx.doi.org/10.1097/CMR.0b013e328270b935DOI Listing
August 2007

Serum VEGF-C is associated with metastatic site in patients with malignant melanoma.

Acta Oncol 2007 ;46(5):678-84

Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland.

Vascular endothelial growth factor-C (VEGF-C) is involved in lymphatic metastatic spread. Metastatic site is a prognostic factor in melanoma. We assessed whether serum levels of VEGF-C are associated with metastatic sites or prognosis in patients treated for stage IV melanoma. The study included 64 patients, who received dacarbazine or four-drug chemotherapy (dacarbazine, vincristine, bleomycin and lomustine; BOLD) both combined with interferon-alfa. Serum samples for VEGF-C were analyzed by ELISA. The patients (n =22) with only skin and subcutaneous metastases had significantly lower mean VEGF-C levels (1 643 pg/ml) then the patients (n =42) with other distant metastases (2 584 pg/ml, Mann-Whitney, p =0.033). VEGF-C levels above the median (1 590 pg/ml) were significantly related to deep lymph node involvement (OR 3.763; 95% CI 1.038 - 13.646, p =0.034). There were no other significant associations between VEGF-C levels and tumour burden, nor were the levels significantly related to the response to therapy or survival. Those eight patients, who had received previous adjuvant IFN-alfa therapy had lower mean VEGF-C levels (1 738 pg/ml) as compared to those 56 patients without previous IFN-alfa therapy (2 335 pg/ml, ANOVA, p =0.026). This is the first study exploring serum VEGF-C in melanoma. VEGF-C might be involved in the deep lymphatic dissemination and progression of melanoma metastasis.
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http://dx.doi.org/10.1080/02841860600965020DOI Listing
September 2007

Survival markers related to bone metastases in prostate cancer.

Anticancer Res 2006 Nov-Dec;26(6C):4879-84

Department of Oncology, Institute of Biomedicine, University of Turku and Turku University Hospital, POB 52, FI-20521 Turku, Finland.

Prognostic value of a bone resorption marker, tartrate-resistant acid phosphatase isoform 5b (TRACP 5b), and two matrix metalloproteinases (MMP-2 and MMP-9) was compared with the standard clinical analyses of total alkaline phosphatase (tALP) and prostate-specific antigen (PSA), in prostate cancer (PC) patients with (BM+) or without (BM-) bone metastases. Diagnostic accuracy evaluation showed the highest area under the curve for tALP (AUC=0.98), followed by PSA (AUC=0.87), TRACP 5b (AUC=0.82), MMP-9 (AUC=0.62) and MMP-2 (AUC=0.53). Significantly shorter survival was observed for patients with tALP (p<0.001), TRACP 5b (p=0.002) and PSA (p<0.001) levels, above the determined cut-off values compared with lower marker levels. In multivariate Cox regression analysis, only tALP and PSA, in addition to Gleason score were independent prognostic factors for survival. Of the three novel markers tested, only TRACP 5b proved to be predictive of survival in PC with bone metastases. MMP-2 and -9 are thus not recommended for further studies in this context.
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January 2007

Association between high collagenase-3 expression levels and poor prognosis in patients with head and neck cancer.

Head Neck 2006 Mar;28(3):225-34

Department of Oncology and Radiotherapy, Turku University Hospital, P.O. Box 52, FIN-20521 Turku, Finland.

Background: Squamous cell carcinoma of the head and neck (HNSCC) is a common cancer type. The ability for curative treatment with surgery and radiotherapy (RT) is usually highly dependent on tumor stage at the time of diagnosis.

Methods: The purpose of this study was to determine whether the expression of a cancer-specific proteinase, collagenase-3 (matrix metalloproteinase-13 [MMP-13]), is associated with survival parameters in patients with HNSCC. We studied MMP-13 expression in tumors of 81 patients with stage I-IV HNSCC treated with surgery alone or in combination with radiotherapy.

Results: We found a subgroup of patients with high MMP-13 expression level in their tumors (>/=90% MMP-13-positive tumor cells) associated with unfavorable prognosis (median overall survival [OS], 11.8 vs 19.6 months, p = .032). In addition, the median disease-specific survival (DSS) time was markedly reduced in this subgroup (13.8 months vs 40.7 months, p = .062). When the subgroup of patients treated with a curative intent was studied, the same association was found in OS (13.8 vs 24.6 months, p = .023) and DSS (p = .004). In addition, there was a trend for association between >/=90% MMP-13 positivity and a recurrent tumor (p = .078) in curatively treated patients.

Conclusions: The short survival time associated with high MMP-13 expression levels could not be predicted by tumor size or local lymph node invasion. These results show that a high MMP-13 expression level is associated with aggressiveness of HNSCC and may have prognostic value in patient evaluation.
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http://dx.doi.org/10.1002/hed.20322DOI Listing
March 2006

Economic evaluation of temozolomide in the treatment of recurrent glioblastoma multiforme.

Pharmacoeconomics 2005 ;23(8):803-15

Department of Social Pharmacy, Center for Pharmaceutical Policy and Economics, University of Kuopio, Kuopio, Finland.

Background: Temozolomide (TMZ) is an oral alkylating agent with demonstrated efficacy as therapy for glioblastoma multiforme (GBM) and anaplastic astrocytoma. TMZ has widely replaced the procarbazine, lomustine plus vincristine (PCV) combination for the treatment of malignant brain tumours as a result of its oral administration and favourable toxicity profile.

Objectives: This study had three related aims. First, the cost effectiveness of TMZ (from the Finnish healthcare payer perspective) was compared with PCV in patients with GBM that had relapsed after primary treatment with surgery and radiotherapy. Second, the probability that TMZ is cost effective, compared with PCV, was estimated at different societal willingness-to-pay levels. Third, the value of new information for reducing the uncertainty related to the choice of treatment between TMZ and PCV was evaluated.

Methods: The cost effectiveness of TMZ and PCV was evaluated using a decision-modelling approach. Incremental cost-effectiveness ratios (ICERs) for cost per gained life-month, progression-free life-month and QALY were calculated. Various information sources were used to acquire parameter values for the model. The efficacy information of both treatments was derived from the medical literature, quality-of-life (QOL) estimates were gathered from Finnish neuro-oncologists using visual analogue scale methods, and data on the use of healthcare resources were collected from hospital databases. The exact prices for resource use were gained from the list of Finnish health service unit costs (year 2001 prices). The model was analysed using second-order Monte Carlo simulation. The value of new information on reducing uncertainty was analysed using the expected value of perfect information (EVPI) approach.

Results: According to the derived ICERs, 1 extra life-month gained with TMZ costs euro2367, 1 extra progression-free life-month costs euro2165, and 1 extra QALY costs euro32 471, compared with PCV, in the treatment of GBM. The probability of TMZ being the most cost-effective choice of treatment was >60% for all levels of willingness to pay >euro5000 per gained life-month. The respective probabilities were >75% for all levels of willingness to pay >euro10 000 per gained progression-free life-month and about 85% for all levels of willingness to pay >euro20 000 per gained quality-adjusted life-month. According to EVPI analysis, future research would potentially be cost effective if the costs of research were euro4.1 million (maximum).

Conclusions: On the basis of this Finnish analysis, TMZ has a high probability of being more cost effective than PCV for patients with GBM. The addition of QOL aspects to the prolonging of survival increases the probability further.
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http://dx.doi.org/10.2165/00019053-200523080-00006DOI Listing
January 2006

High serum levels of matrix metalloproteinase-9 and matrix metalloproteinase-1 are associated with rapid progression in patients with metastatic melanoma.

Clin Cancer Res 2005 Jul;11(14):5158-66

Department of Oncology and Radiotherapy, Turku University Hospital, Finland.

Purpose: Matrix metalloproteinases (MMP) are proteolytic enzymes that play an important role in various aspects of cancer progression. In the present work, we have studied the prognostic significance of serum levels of gelatinase B (MMP-9), collagenase-1 (MMP-1), and collagenase-3 (MMP-13) in patients with advanced melanoma.

Experimental Design: Total pretreatment serum levels of MMP-9 in 71 patients and MMP-1 and MMP-13 in 48 patients were determined by an assay system based on ELISA. Total MMP levels were also assessed in eight healthy controls. The active and latent forms of MMPs were defined by using Western blot analysis and gelatin zymography.

Results: Patients with high serum levels of MMP-9 (> or = 376.6 ng/mL; n = 19) had significantly poorer overall survival (OS) than patients with lower serum MMP-9 levels (n = 52; median OS, 29.1 versus 45.2 months; P = 0.033). High MMP-9 levels were also associated with visceral or bone metastasis (P = 0.027), elevated serum alkaline phosphatase level (P = 0.0009), and presence of liver metastases (P = 0.032). Serum levels of MMP-1 and MMP-13 did not correlate with OS. MMP-1 and MMP-9 were found mainly in latent forms in serum, whereas the majority of MMP-13 in serum was active (48 kDa) form. MMP-13 was found more often in active form in patients (mean, 99% of the total MMP-13 level) than in controls (mean, 84% of the total MMP-13 level; P < 0.0001). After initiating the therapy, patients with elevated levels of MMP-1 (> or = 29.8 ng/mL, n = 10) progressed more rapidly than patients with lower levels (median, 1.9 versus 3.5 months; P = 0.023). Serum levels of MMP-9 and MMP-13 did not correlate with the time to progression (TTP). In multivariate analysis with age and gender, MMP-9 or MMP-1 turned out to be independent prognostic factors for OS [P = 0.039; hazard ratio (HR), 1.8; 95% confidence interval (95% CI), 1.03-3.3] or TTP (P = 0.023; HR, 2.7; 95% CI, 1.15-6.4), respectively.

Conclusions: Our findings provide evidence that MMP-1, MMP-9, and MMP-13 play important roles at different phases of metastatic melanoma spread and that serum MMP-9, in particular, could have clinical value in identifying patients at high risk for melanoma progression.
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http://dx.doi.org/10.1158/1078-0432.CCR-04-2478DOI Listing
July 2005

Matrix metalloproteinases as therapeutic targets in cancer.

Curr Cancer Drug Targets 2005 May;5(3):203-20

Department of Oncology and Radiotherapy, Turku University Hospital, Kiinamyllynkatu 4-8, FIN-20520 Turku, Finland.

Degradation of extracellular matrix is crucial for malignant tumor growth, invasion, metastasis and angiogenesis. Matrix metalloproteinases (MMPs) are a family of zinc-dependent neutral endopeptidases collectively capable of degrading essentially all matrix components. Elevated levels of distinct MMPs can be detected in tumor tissue or serum of patients with advanced cancer, and their role as prognostic indicators in cancer has been widely examined. In addition, therapeutic intervention in tumor growth and invasion based on inhibition of MMP activity is under intensive investigation and several MMP inhibitors (MMPIs) are in clinical cancer trials. Even though results of the first clinical trials in advanced cancer have been mostly disappointing, there are also positive results. Recent observations show, that certain MMPs limit tumor growth. Therefore, identification of proper MMPs for therapeutic intervention with array-based molecular classifications of tumors and targeting these with more specific MMPIs in combination with conventional chemotherapy is expected to provide a feasible approach for cancer therapy. MMPIs represent a totally different therapeutic modality from proven anti-cancer drugs and thus traditional approaches to evaluate drug efficiency cannot be used without modification. In this review, we discuss the current view on the feasibility of MMPs as targets for therapeutic intervention in cancer.
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http://dx.doi.org/10.2174/1568009053765799DOI Listing
May 2005

[Prognostic factors and improving treatment of cutaneous melanoma].

Duodecim 2004 ;120(12):1445-56

TYKS:n syöpätautien klinikka, Turku.

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January 2005

Integrin chains beta1 and alphav as prognostic factors in human metastatic melanoma.

Melanoma Res 2004 Feb;14(1):29-37

Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland.

The expression pattern of integrin-type cell adhesion receptors is often changed during malignant transformation. In the present work, we studied the prognostic significance of beta1 and alphav integrin chains for survival of patients with metastatic melanoma. The expression levels of beta1 integrin were also compared with those of Bcl-2, an anti-apoptotic protein, the presence of which is associated with treatment response and survival in melanoma. The expression of beta1 and alphav integrins in 68 melanoma metastases obtained from 55 patients treated with combined chemoimmunotherapy was studied by immunohistochemistry using anti-beta1 and anti-alphav antibodies. The patients were divided into two groups (using a cut-off point of >/= 81%) for beta1 integrin expression levels and into three categories (negative/low, median, high) for alphav integrin expression levels. All tumours were positive for beta1 integrin, and the tumours (n = 6) which had the highest alphav score were also strongly positive for beta1 (94%; P = 0.0055). Patients (n = 43) with 80% or less beta1 integrin-positive tumour cells in their samples had a median disease-free survival (DFS) of 17.0 months, and patients (n = 12) with 81% or more beta1 integrin-positive tumour cells had a DFS of only 5.7 months (P = 0.0001). Patients (n = 32) with low alphav integrin expression levels had shorter DFS (median 12.3 months; P = 0.0146) than patients (n = 20) with median expression levels (median 16.7 months; P = 0.0146). However, three patients who had a very strong alphav expression in their tumours had a median DFS of only 1.8 months (P = 0.0146). Median level expression of beta1 integrin was associated with the presence of Bcl-2 in tumour cells (P = 0.0033). Our results suggest that beta1 and alphav integrin chains are independently expressed in metastatic melanoma and may have an effect on the metastatic potential of melanoma cells.
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http://dx.doi.org/10.1097/00008390-200402000-00005DOI Listing
February 2004

Low collagenase-1 (MMP-1) and MT1-MMP expression levels are favourable survival markers in advanced colorectal carcinoma.

Oncology 2003 ;65(4):337-46

Department of Oncology and Radiotherapy, Turku University Central Hospital, Turku, Finland.

Objective: Extracellular matrix degradation is required for invasive growth and metastasis formation in colorectal carcinoma; therefore, we examined matrix metalloproteinases expression (MMP-1, MMP-13 and MT1-MMP) and apoptosis in tumours from 49 patients with advanced colorectal disease.

Methods: MMP expression was determined immunohistochemically and apoptotic index (AI) was ascertained using the TUNEL assay.

Results: Low levels of MT1-MMP, MMP-1 and AI were found to be favourable markers significantly associated with longer survival. MT1-MMP expression levels below the median (
Conclusions: These findings reveal that MT1-MMP and MMP-1 expression levels and AI are useful prognostic indicators in advanced colorectal carcinoma and suggest that markers of MMP expression might be used in identifying patients who would benefit from new treatment modalities involving MMP inhibitors.
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http://dx.doi.org/10.1159/000074647DOI Listing
February 2004

New prognostic factors and developing therapy of cutaneous melanoma.

Ann Med 2003 ;35(2):66-78

Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland.

The multiple molecular alterations underlying the neoplastic process and clinical characteristics of cutaneous melanoma are currently under intensive investigation. Recent studies have demonstrated that the levels of melanoma-associated proteins in tumor tissue or in patient serum can serve as new markers to predict disease outcome. Similarly, the expression of thousands of genes in melanoma tumors can be surveyed simultaneously using DNA arrays, allowing molecular profiling of individual tumors, which gives the possibility of classifying melanomas based on their biological diversity. Large clinical studies have also identified multiple prognostic factors, such as tumor ulceration, and led to development of a new, more precise melanoma staging system, which emphasizes the biological characteristics of the primary disease. These new findings may have an important role in earlier measurement of the clinical response and provide a basis for tailored melanoma therapy, the development of which will also be discussed in this review.
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http://dx.doi.org/10.1080/07853890310009980DOI Listing
October 2003

Matrix metalloproteinases in cancer: prognostic markers and therapeutic targets.

Int J Cancer 2002 May;99(2):157-66

Department of Oncology and Radiotherapy, Turku University Central Hospital, Turku, Finland.

Degradation of extracellular matrix is crucial for malignant tumour growth, invasion, metastasis and angiogenesis. Matrix metalloproteinases (MMPs) are a family of zinc-dependent neutral endopeptidases collectively capable of degrading essentially all matrix components. Elevated levels of distinct MMPs can be detected in tumour tissue or serum of patients with advanced cancer and their role as prognostic indicators in cancer is studied. In addition, therapeutic intervention of tumour growth and invasion based on inhibition of MMP activity is under intensive investigation and several MMP inhibitors are in clinical trials in cancer. In this review, we discuss the current view on the feasibility of MMPs as prognostic markers and as targets for therapeutic intervention in cancer.
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http://dx.doi.org/10.1002/ijc.10329DOI Listing
May 2002

High expression levels of collagenase-1 and stromelysin-1 correlate with shorter disease-free survival in human metastatic melanoma.

Int J Cancer 2002 Feb;97(4):432-8

Department of Oncology and Radiotherapy, Turku University Central Hospital, Turku, Finland.

Matrix metalloproteinases (MMPs) are proteolytic enzymes capable of degrading extracellular matrix. Their role has been emphasized in tumor invasion, metastasis and tumor-induced angiogenesis. We studied the expression of collagenase-1 (MMP-1), stromelysin-1 (MMP-3) and collagenase-3 (MMP-13) in 70 melanoma metastases obtained from 56 patients treated with combined chemoimmunotherapy. The patients were divided into 2 groups using a cut-off point of 0% for MMP-1 expression and 20% for MMP-3 expression. We found that patients with MMP-1 positive metastases (n = 38) had significantly shorter disease-free survival compared to patients with MMP-1 negative metastases (n = 18) (median 11.2 vs. 17.0 months, p = 0.0383). The disease-free survival of patients with high levels of MMP-3 expression in their metastases (> or = 20% positive tumor cells, n = 14) was also significantly shorter compared to patients with lower levels of expression (n = 42) (median 5.1 vs. 14.0 months, p = 0.0294). The expression of MMP-13 did not correlate to survival parameters. We also found that the presence of melanin, a pigment produced by melanocytes, correlated with high expression levels of MMP-1 (p = 0.0002), MMP-3 (p < 0.0001) and MMP-13 (p = 0.0009). The high expression levels of MMP-13 were also associated with the presence of visceral metastases (p = 0.0284). Our findings suggest that MMP-1 and -3 may have a special role in melanoma metastasis formation and thus they could be used to measure the biological activity of the disease.
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http://dx.doi.org/10.1002/ijc.1636DOI Listing
February 2002

High collagenase-1 expression correlates with a favourable chemoimmunotherapy response in human metastatic melanoma.

Melanoma Res 2001 Apr;11(2):157-66

Department of Oncology/Radiotherapy, Turku University Central Hospital, Finland.

Matrix metalloproteinases (MMPs) are proteolytic enzymes that can degrade extracellular matrix and thus enhance metastasis. We have studied the expression of two collagenolytic MMPs in 37 samples obtained from 26 patients treated for metastatic melanoma. Interestingly, the samples showed a different expression pattern of collagenase-1 (MMP-1) and collagenase-3 (MMP-13). The samples with high expression levels of MMP-1 (n = 18) were more frequently MMP-13 negative (14 out of 18), whereas those with low expression levels of MMP-1 (n = 15) were predominantly positive for MMP-13 (nine out of 15) (P = 0.027). High expression levels of MMP-1 were associated with a favourable response to chemoimmunotherapy. Responders (n = 13) frequently had intensively MMP-1-expressing metastases (nine out of 13), especially those who achieved a complete response (five out of six). Response failures (n = 7) mainly had metastases with a low intensity of MMP-1 expression (six out of seven) (P = 0.019). There was a tendency towards longer survival among patients with intensively MMP-1-expressing tumours (median 14.3 versus 6.7 months, P = 0.068). The high expression levels of MMP-1 correlated with low MIB-1 (to nuclear antigen Ki-67) (P = 0.019) and positivity for MMP-13 was associated with high MIB-1 expression (P = 0.00048), suggesting that their different expression patterns may affect tumour growth and contribute to differences in patient survival.
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http://dx.doi.org/10.1097/00008390-200104000-00011DOI Listing
April 2001

Prognostic value of beta1 integrin expression in metastatic melanoma.

Melanoma Res 2000 Jun;10(3):243-51

Department of Medical Biochemistry and Medicity Research Laboratory, University of Turku, Finland.

The expression of integrin-type cell adhesion receptors is frequently changed in malignant transformation. Despite their important role in cancer cell behaviour, the value of integrins as prognostic markers is mostly unknown. We have examined the expression of beta1 integrins in 38 metastatic melanomas obtained from 27 patients treated with combined chemoimmunotherapy. On the basis of beta1 integrin expression, the melanoma samples were divided into two groups: beta1-negative tumours (<10% beta1 integrin immunostained cells) and beta1-positive tumours (with > or = 10% positive cells). Patients with beta1-positive tumours (n = 15) had significantly longer disease-free survival (median 38 versus 7 months, P < 0.0001) and overall survival (median 70 versus 23 months, P = 0.0001) evaluated after the diagnosis of primary disease compared with patients with beta1-negative metastases (n = 11). Moreover, the survival of the patients with beta1-positive tumours after the initiation of chemoimmunotherapy was significantly prolonged (median 18 versus 9 months, P = 0.017). The independent nature of beta1 integrin expression as a significant prognostic factor for survival after therapy was confirmed using Cox's multivariate analysis (P = 0.014). Our results indicate that the expression of beta1 integrins might have some major tumour growth regulatory role and can be used as a predictor for prognosis in patients with metastatic melanoma.
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June 2000

Echovirus 1 infection induces both stress- and growth-activated mitogen-activated protein kinase pathways and regulates the transcription of cellular immediate-early genes.

Virology 1998 Oct;250(1):85-93

MediCity Research Laboratory, Department of Virology, Department of Medical Biochemistry, University of Turku, Tykistökatu 6A, Turku, FIN-20520, Finland.

We have previously shown that echovirus 1 (EV1) infection increases the mRNA levels of cellular immediate-early (IE) genes in host cells. Here we provide further evidence that the induction of junB, c-jun, and c-fos genes is due to active viral macromolecular synthesis rather than to the interaction of EV1 with its receptor, alpha2beta1 integrin. Nuclear run-on transcription assays indicated that differences in mRNA levels in infected and uninfected cells are brought about by regulation at the transcriptional level. EV1 infection induced the phosphorylation of both the stress-related p38 mitogen-activated protein kinase (MAPK) and the growth signal-related ERK1/2 MAPKs. Studies with selective MAPK inhibitors revealed that p38 was the main inducer of junB expression, whereas both MAPK pathways were involved in the induction of c-fos. Activation of AP-1 genes was also observed to occur during infections with other enteroviruses and with Semliki Forest A7(74) virus, suggesting that the phosphorylation of MAPKs and induction of AP-1 gene expression may be important regulators of host cell behavior during viral infections.
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http://dx.doi.org/10.1006/viro.1998.9343DOI Listing
October 1998

Integrin alpha 2 beta 1 in tumorigenic human osteosarcoma cell lines regulates cell adhesion, migration, and invasion by interaction with type I collagen.

Cell Growth Differ 1996 Apr;7(4):439-47

Department of Medical Biochemistry, University of Turku, Turku, Finland.

Human osteosarcomas are aggressive bone tumors. Here we propose that their progression requires altered cell interaction with extracellular matrix. Since type I collagen is the main matrix molecule found in bone and thus obligated to interact with tumor cells, we analyzed the expression and function of different integrin-type collagen receptors in tumor cell-collagen interaction by using eight human osteogenic sarcoma (HOS) cell lines. Virally (Kirsten sarcoma virus) transformed derivatives of HOS cells (KHOS-NP) and chemically [N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)] transformed tumorigenic subclones of human osteogenic sarcoma cells (HOS-MNNG) expressed alpha 2 beta 1 integrin in remarkably larger amounts than the six other nontumorigenic cell lines (HOS, MG-63, Saos-2, KHOS-240, KHOS-312, and G292). Concomitantly, Mg(2+)-dependent adhesion of tumorigenic cells to type I collagen was increased. We also show that the migration of tumorigenic cells on and invasion through type I collagen is faster than that of HOS cells. HOS cells forced to express alpha 2 integrin by cDNA transfections showed increased Mg(2+)-dependent cell adhesion to type I collagen and also accelerated migration and invasion rate, indicating that the overexpression of alpha 2 beta 1 integrin in tumorigenic cells alone explains the altered cell-collagen interaction. Finally, HOS cells forced to express alpha 2 integrin subunit did not grow s.c. in athymic mice, suggesting that overexpression of alpha 2 integrin is not efficient to make these cells tumorigenic.
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April 1996

Antibody against human alpha 1 beta 1 integrin inhibits HeLa cell adhesion to laminin and to type I, IV, and V collagens.

Biochem Biophys Res Commun 1995 Apr;209(1):205-12

Department of Medical Biochemistry, University of Turku, Finland.

In HeLa cells beta 1 integrin forms heterodimers with alpha 1, alpha 2, alpha 3, alpha 5 and alpha 6 integrin subunits. Integrin alpha v beta 5 can also be detected. A monoclonal antibody SR-84 identified the alpha 1 integrin subunit in immunoprecipitation assays and inhibited alpha 1-related cell adhesion to different matrix proteins, laminin-1 and type I, IV, and V collagens, whereas its effect on adhesion to type II collagen was marginal. HeLa cells do not attach to type VI collagen. The presence of magnesium was essential for HeLa cell adhesion, whereas calcium alone was not sufficient and high concentrations of calcium even counteracted the effect of magnesium. Cell adhesion to type I collagen was sensitive to changes in pH, unlike cell adhesion to type IV collagen. We conclude that SR-84 is a valuable tool to study alpha 1 integrin-related functions, and that in HeLa cells alpha 1 beta 1 integrin is a magnesium-dependent receptor for type I, IV, and V collagens but not for type II and VI collagens.
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http://dx.doi.org/10.1006/bbrc.1995.1490DOI Listing
April 1995

Transforming growth factor-beta regulates collagen gel contraction by increasing alpha 2 beta 1 integrin expression in osteogenic cells.

J Biol Chem 1995 Jan;270(1):376-82

Department of Medical Biochemistry, University of Turku, Finland.

The contraction of floating collagen gels is suggested to mimic the reorganization of collagenous matrix during development and tissue healing. Here, we have studied two osteogenic cell lines, namely MG-63 and HOS, and a chemically transformed subclone of HOS cells, HOS-MNNG. Transforming growth factor-beta (TGF-beta), a putative regulator of bone fracture healing, increased collagen gel contraction by MG-63 and HOS-MNNG, but not by HOS cells. Our data show that TGF-beta-induced fibronectin synthesis is not sufficient for the process. Instead, anti-beta 1 integrin antibodies could prevent the contraction. There are three different integrin heterodimers that are known to mediate the cell-collagen interaction, namely alpha 1 beta 1, alpha 2 beta 1, and alpha 3 beta 1. In MG-63 cells TGF-beta increased the expression of alpha 2 beta 1 integrin and decreased the expression of alpha 3 beta 1 integrin, whereas alpha 1 beta 1 integrin is not expressed. HOS cells had no alpha 2 beta 1 integrin, neither did TGF-beta induce its expression. However, HOS-MNNG cells expressed more alpha 2 beta 1 integrin when treated with TGF-beta. Thus, we suggest that the mechanism of the enhanced collagen gel contraction by TGF-beta is the increased expression of alpha 2 beta 1 integrin heterodimer. To further test this hypothesis, we expressed a full-length alpha 2 integrin cDNA in HOS cells and in MG-63 cells. We obtained HOS cell clones that expressed alpha 2 beta 1 heterodimer, and the ability of these cells to contract collagen gels was greatly enhanced. Furthermore, the contraction by MG-63 cells transfected with alpha 2 integrin cDNA was enhanced, and the contraction by cells transfected with antisense oriented alpha 2 integrin cDNA was decreased. Thus, both in MG-63 and HOS cells the increased alpha 2 integrin expression alone was sufficient for the enhanced contraction of collagen gels. Furthermore, the amount of alpha 2 integrin is critical for the process, and its decrease leads to diminished ability to contract gels.
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http://dx.doi.org/10.1074/jbc.270.1.376DOI Listing
January 1995
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