p53 mutations and high protein expression are associated with adverse prognosis in several lympho... more p53 mutations and high protein expression are associated with adverse prognosis in several lymphoma subtypes. Matrix metalloproteinase-9 (MMP-9) has also been found to correlate with poor survival in all lymphomas studied. The data concerning the clinical role of protein expression of p53 or gelatinases and their inhibitors in follicular lymphoma are rare. The purpose of this study was to evaluate the prognostic and clinical implications of the immunoreactive proteins p53, MMP-2, MMP-9, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and TIMP-2 in follicular lymphoma. The material consisted of 67 patients with primarily non-transformed follicular lymphoma. Diagnostic lymph node tissue sections of patients were stained by immunohistochemical method using specific monoclonal antibodies. p53 over-expression was detected in 8 (12%) out of 67 cases. p53 over-expression correlated with high grade (P = 0.011), bulky tumour (P = 0.031) and forthcoming transformation (P = 0.001). It also correlated with poor overall (P = 0.001) and cause-specific survival (P = 0.010) in multivariate analysis and had a strong inverse correlation with time to transformation (P < 0.001). MMP-2, MMP-9 and TIMP-2 expression correlated with high grade. MMP-9 positivity in centroblasts correlated with good chemotherapy response (P = 0.019), but it was not prognostic for survival. MMP-2, TIMP-1 or TIMP-2 did not associate with survival, either. In this study, p53 over-expression predicted both transformation to diffuse large B-cell lymphoma and poorer overall and cause-specific survival of patients with follicular lymphoma. Expression of gelatinases or their inhibitors did not have any significant correlations with prognosis, although MMP-9 predicted a good response to first-line chemotherapy.
Matrix metalloproteinases (MMPs) are involved in tumor growth and spreading. Here, we investigate... more Matrix metalloproteinases (MMPs) are involved in tumor growth and spreading. Here, we investigated the tumor immunoreactive protein of MMP-2, MMP-9 and TIMP-1 as well as the levels of circulating total TIMP-1 and MMP-2/TIMP-2-complex as prognostic factors in lung cancer patients. The material included 59 patients, 30 with a squamous cell carcinoma, 21 with an adenocarcinoma and eight with other histology.
Dendritic cells play an integral role in the normal physiological function of lymph nodes. They p... more Dendritic cells play an integral role in the normal physiological function of lymph nodes. They participate in the clonal expansion and evolution of B-cells [1] and induce specific immune responses [2]. In Hodgkin’s lymphoma, the existence of an intact dendritic cell reticulum has been shown to be a positive prognostic indicator in a retrospective Hodgkin’s lymphoma set treated mainly with radiotherapy [3]. The aim of the present study was to explore whether preservation of the denritic cell network could serve as a prognostic indicator also in Hodgkin’s lymphoma patients treated with modern treatment modalities. The series consisted of 63 adult patients (15 – 88 years old) with histologically proven Hodgkin’s lymphoma treated at the Department of Radiotherapy and Oncology, Oulu University Hospital, between January 1990 and December 1997. The patients were diagnosed and staged according to the routine lymphoma staging procedures. Thirty-five patients were treated with either chemotherapy or combined chemoand radiotherapy and 28 patients recieved radiotherapy alone. Paraffin sections were stained for cystatin A using a monoclonal anti-cystatin A antibody (commercially available from Sigma Chemical Co and from Alexis Biochemicals) diluted 1/800 and 1/1600 in PBS containing 1% bovine serum albumin according to methods described earlier [3]. Also sample evaluation and statistical methods followed the previous scheme. In the present study, using a monoclonal cystatin A antibody, we were unable to confirm earlier findings of the prognostic significance of preserved dendritic cell network in Hodgkin’s lymphoma in the whole material. However, when considering patients treated with radiation therapy alone a trend towards worse survival could be detected in patients with a disrupted dendritic cell reticulum, not falling far apart from previous studies. No patients with a preserved dendritic cell reticulum (8 patients) died of Hodgkin’s lymphoma compared to 5 of 20 with a disrupted dendritic cell reticulum. Alavaikko et al. have published a study of 139 Hodgkin’s lymphoma patients treated between the years 1963 and 1989 at our hospital and Tampere University Hospital, and they found a preserved dendritic cell network to be of marked prognostic relevance [3]. Our results are not in line with their findings. However, this new set of patients were all treated in the 1990’s. Between these 2 study periods, there have been remarkable changes in the diagnostic and treatment modalities of Hodgkin’s lymphoma, and survival has been steadily increasing. The most important changes have been the development and wide adoption of new effective chemotherapeutic combinations, such as ABVD and MOPP/ABVD, and the development of highdose treatment with stem cell support for patients with refractory or relapsing disease. These changes may have affected the prognostic importance of the different biological features of the disease. It could be anticipated that, at the time when large-field radiation therapy was the primary treatment modality, the significance of immune response to control the microscopic residual disease outside the treatment field would have been of a major prognostic significance. On the other hand, in patients treated with modern multi-agent chemotherapy regimens, the tumors chemosensitivity is probably a much more significant discriminating factor in prognosis. In fact, we saw a trend toward poorer survival in the patients
Diffuse large B-cell lymphoma (DLBCL) is an aggressive and potentially fatal disease. Prediction ... more Diffuse large B-cell lymphoma (DLBCL) is an aggressive and potentially fatal disease. Prediction of risk of relapse is based on clinical markers. There is a need for more accurate biomarkers to select patients for more aggressive first-line treatments. Peroxiredoxins (Prxs) are a family of potent antioxidant proteins. Their prognostic role in DLBCL is unknown. Altogether, 103 diagnostic biopsy samples from patients with DLBCL were immunohistochemically stained for Prxs I, II, III, V and VI. Strong Prx VI expression was associated with the presence of B-symptoms. There were no other significant associations with traditional risk factors. Five-year disease-specific survival was 68.6% in patients with high cytoplasmic Prx VI intensity vs 97.0% in those with low intensity. In multivariate analysis, high Prx VI expression (HR 12.846, 95% CI 1.722 to 95.807, p=0.013) was an independent risk factor of lymphoma-associated death not related to International Prognostic Index score (HR 2.514, 95% CI 1.040 to 6.073, p=0.041). High intensity of cytoplasmic Prx VI expression in pretreatment DLBCL samples predicts worse outcome in patients with DLBCL. Whether Prx VI is associated with chemoresistance, and therefore a poorer outcome, needs to be evaluated. If Prx VI is a predictive marker and it proves causality, it would be crucial to study Prx VI ability to become a target enzyme for treatment.
The molecular mechanisms underlying prostate carcinogenesis are poorly understood. Prostatic acid... more The molecular mechanisms underlying prostate carcinogenesis are poorly understood. Prostatic acid phosphatase (PAP), a prostatic epithelial secretion marker, has been linked to prostate cancer since the 1930's. However, the contribution of PAP to the disease remains controversial. We have previously cloned and described two isoforms of this protein, a secretory (sPAP) and a transmembrane type-I (TMPAP). The goal in this work was to understand the physiological function of TMPAP in the prostate. We conducted histological, ultra-structural and genome-wide analyses of the prostate of our PAP-deficient mouse model (PAP 2/2) with C57BL/6J background. The PAP 2/2 mouse prostate showed the development of slow-growing non-metastatic prostate adenocarcinoma. In order to find out the mechanism behind, we identified PAP-interacting proteins byyeast two-hybrid assays and a clear result was obtained for the interaction of PAP with snapin, a SNAREassociated protein which binds Snap25 facilitating the vesicular membrane fusion process. We confirmed this interaction by co-localization studies in TMPAP-transfected LNCaP cells (TMPAP/LNCaP cells) and in vivo FRET analyses in transient transfected LNCaP cells. The differential gene expression analyses revealed the dysregulation of the same genes known to be related to synaptic vesicular traffic. Both TMPAP and snapin were detected in isolated exosomes. Our results suggest that TMPAP is involved in endo-/exocytosis and disturbed vesicular traffic is a hallmark of prostate adenocarcinoma.
Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma with diverse outcomes. Concurrent... more Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma with diverse outcomes. Concurrent translocation of MYC and BCL-2 and/or BCL-6, and concurrent immunohistochemical (IHC) high expression of MYC and BCL-2, have been linked to unfavorable treatment responses. TP53-mutated DLBCL has also been linked to worse outcome. Our aim was to evaluate the aforementioned issues in a cohort of 155 patients uniformly treated with R-CHOP-like therapies. We performed direct sequencing of TP53 exons 5, 6, 7 and 8 as well as fluorescence in-situ hybridization (FISH) of MYC, BCL-2 and BCL-6, and IHC of MYC, BCL-2 and BCL-6. In multivariate analysis, TP53 mutations in L3 and loop-sheet helix (LSH) associated with a risk ratio (RR) of disease-specific survival (DSS) of 8.779 (p = 0.022) and a RR of disease-free survival (DFS) of 10.498 (p = 0.011). In IHC analysis BCL-2 overexpression was associated with inferior DFS (p = 0.002) and DSS (p = 0.002). DLBCL with BCL-2 and MYC overexpression conf...
Central nervous system (CNS) relapse occurs in around 5% of diffuse large B‐cell lymphoma (DLBCL)... more Central nervous system (CNS) relapse occurs in around 5% of diffuse large B‐cell lymphoma (DLBCL) cases. No biomarkers to identify high‐risk patients have been discovered. We evaluated the expression of lymphocyte‐guiding chemokine receptors in systemic and CNS lymphomas. Immunohistochemical staining for CXCR4, CXCR5, CCR7, CXCL12, and CXCL13 was performed on 89 tissue samples, including cases of primary central nervous system lymphoma (PCNSL), secondary CNS lymphoma (sCNSL), and systemic DLBCL. Also, 10 reactive lymph node samples were included. Immunoelectron microscopy was performed on two PCNSLs, one sCNSL, one systemic DLBCL, and one reactive lymph node samples, and staining was performed for CXCR4, CXCR5, CXCL12, and CXCL13. Chi‐square test was used to determine correlations between clinical parameters, diagnostic groups, and chemokine receptor expression. Strong nuclear CXCR4 positivity correlated with systemic DLBCL, whereas strong cytoplasmic CXCR5 positivity correlated wit...
Primary central nervous system lymphoma (PCNSL) is a rare brain tumour with a dismal prognosis. S... more Primary central nervous system lymphoma (PCNSL) is a rare brain tumour with a dismal prognosis. Several phase II studies with high-dose methotrexate-based regimens have shown promising early results, but in all hospital-based data published so far, the disease outcome is poor. We performed a hospital-based retrospective analysis to evaluate the long-term results of the Nordic type of Bonn chemotherapy regimen in PCNSL patients. The study included 54 patients with newly diagnosed PCNSL who received chemotherapy with curative intent as their first-line treatment. We found promising response rates, 76% of the patients achieving CR and 22% patients achieving PR, with corresponding two-year EFS 53% and OS 76%. However, with longer follow-up a constant pattern of relapses was observed with only one patient remaining in primary remission after 60 months. The finding suggests that basic biological differences exist between PCNSL and systemic diffuse large B-cell lymphoma and there is a need for consolidation or maintenance therapy after achieving a remission in patients with PCNSL.
Although oxidative stress plays an important role in the biology of solid malignant tumors, littl... more Although oxidative stress plays an important role in the biology of solid malignant tumors, little is known about oxidative stress in hematological malignancies. In this study, we evaluated the immunohistochemical expression and clinical correlations of oxidative stress markers and several essential antioxidant enzymes in B-cell lymphomas. Paraffin-embedded diagnostic tissue samples from 18 diffuse large B-cell lymphomas (DLBCL), 18 follicular lymphomas (FL), 19 Hodgkin lymphomas (HL), 7 chronic lymphocytic leukemias (CLL), 7 mantle cell lymphomas (MCL) and 7 mucosa-associated lymphoid tissue (MALT) lymphomas, together with samples from 6 reactive lymph nodes were stained for oxidative stress markers 8-hydroxydeoxyguanosine (8-OHdG) and nitrotyrosine and antioxidant enzymes manganese superoxide dismutase (MnSOD), thioredoxin (Trx) and γ-glutamyl cysteine synthetase (γ-GCS). There was increased 8-OHdG reactivity in DLBCL compared to more indolent lymphomas and reactive lymph nodes. Positivity for Trx was most intense in HL. In DLBCL, positivity for 8-OHdG and nitrotyrosine associated with shorter survival (p = 0.032 and p = 0.026, respectively). This study showed increasing expression of oxidative stress markers and antioxidant enzymes in a series of lymph node samples evolving from reactive lymph nodes to indolent and aggressive lymphomas. These markers seem to have strong prognostic value, but this has to be verified in larger studies.
Dendritic cells play an integral role in the normal physiological function of lymph nodes. They p... more Dendritic cells play an integral role in the normal physiological function of lymph nodes. They participate in the clonal expansion and evolution of B-cells [1] and induce specific immune responses [2]. In Hodgkin’s lymphoma, the existence of an intact dendritic cell reticulum has been shown to be a positive prognostic indicator in a retrospective Hodgkin’s lymphoma set treated mainly with radiotherapy [3]. The aim of the present study was to explore whether preservation of the denritic cell network could serve as a prognostic indicator also in Hodgkin’s lymphoma patients treated with modern treatment modalities. The series consisted of 63 adult patients (15 – 88 years old) with histologically proven Hodgkin’s lymphoma treated at the Department of Radiotherapy and Oncology, Oulu University Hospital, between January 1990 and December 1997. The patients were diagnosed and staged according to the routine lymphoma staging procedures. Thirty-five patients were treated with either chemotherapy or combined chemoand radiotherapy and 28 patients recieved radiotherapy alone. Paraffin sections were stained for cystatin A using a monoclonal anti-cystatin A antibody (commercially available from Sigma Chemical Co and from Alexis Biochemicals) diluted 1/800 and 1/1600 in PBS containing 1% bovine serum albumin according to methods described earlier [3]. Also sample evaluation and statistical methods followed the previous scheme. In the present study, using a monoclonal cystatin A antibody, we were unable to confirm earlier findings of the prognostic significance of preserved dendritic cell network in Hodgkin’s lymphoma in the whole material. However, when considering patients treated with radiation therapy alone a trend towards worse survival could be detected in patients with a disrupted dendritic cell reticulum, not falling far apart from previous studies. No patients with a preserved dendritic cell reticulum (8 patients) died of Hodgkin’s lymphoma compared to 5 of 20 with a disrupted dendritic cell reticulum. Alavaikko et al. have published a study of 139 Hodgkin’s lymphoma patients treated between the years 1963 and 1989 at our hospital and Tampere University Hospital, and they found a preserved dendritic cell network to be of marked prognostic relevance [3]. Our results are not in line with their findings. However, this new set of patients were all treated in the 1990’s. Between these 2 study periods, there have been remarkable changes in the diagnostic and treatment modalities of Hodgkin’s lymphoma, and survival has been steadily increasing. The most important changes have been the development and wide adoption of new effective chemotherapeutic combinations, such as ABVD and MOPP/ABVD, and the development of highdose treatment with stem cell support for patients with refractory or relapsing disease. These changes may have affected the prognostic importance of the different biological features of the disease. It could be anticipated that, at the time when large-field radiation therapy was the primary treatment modality, the significance of immune response to control the microscopic residual disease outside the treatment field would have been of a major prognostic significance. On the other hand, in patients treated with modern multi-agent chemotherapy regimens, the tumors chemosensitivity is probably a much more significant discriminating factor in prognosis. In fact, we saw a trend toward poorer survival in the patients
Hodgkin lymphoma treatments are largely based on the generation of reactive oxygen species, but i... more Hodgkin lymphoma treatments are largely based on the generation of reactive oxygen species, but increased expression of antioxidant enzymes may contribute to chemoresistance. The aims of this study were: to define the extent and prognostic value of oxidative stress marker and antioxidant enzyme expression in Hodgkin lymphomas; and to investigate a potential association between antioxidant enzymes and chemoresistance. We immunohistochemically assessed expression of peroxiredoxin (Prx) II, Prx III, Prx V, Prx VI, manganese superoxide dismutase (MnSOD), 8-hydroxydeoxyguanosine (8-OHdG) and nitrotyrosine in 99 cases of uniformly treated Hodgkin lymphoma. Localization of 8-OHdG was assessed using transmission electron microscopy, which demonstrated expression in the cytosol and mitochondria. 8-OHdG expression in Reed-Sternberg (RS) cells was associated with advanced stage (P = 0.006) and a lower International Prognostic Score (P = 0.004). Prx III expression in reactive cellular infiltrate was associated with advanced stage (P = 0.002) and B-symptoms (P = 0.0006). Strong cytoplasmic Prx V immunostaining was associated with a low rate of complete response to chemotherapy (P = 0.043). MnSOD immunostaining in RS cells was related to advanced stage (P = 0.031) and to poorer relapse-free survival (RFS) (P = 0.033). Low 8-OHdG expression in the nuclei of RS cells was a predictor of poorer RFS (P = 0.038). Both 8-OHdG and MnSOD were also significant RFS predictors in multivariate analysis. Our results suggest that significant oxidative stress exists in Hodgkin lymphomas, both in RS cells and in reactive cellular infiltrates. Mitochondrial antioxidant enzymes are induced in the most aggressive forms of the disease, and they may play some part in chemoresistance.
Biological roles and prognostic values of the epithelial-mesenchymal transition-mediating transcr... more Biological roles and prognostic values of the epithelial-mesenchymal transition-mediating transcription factors Twist, ZEB1 and Slug in diffuse large B-cell lymphoma Aims: To evaluate the biological roles and prognostic significance of the epithelial-mesenchymal transition (EMT)-mediating transcription factors (TFs) Twist, ZEB1 and Slug in patients with diffuse large B-cell lymphoma (DLBCL). EMT has been shown to enhance solid tumour metastasis, invasion, and proliferation. Methods and results: Expression of Twist, ZEB1 and Slug was evaluated immunohistochemically in eight samples from reactive lymphoid tissues and in diagnostic samples from 102 DLBCL patients treated with curative intent with R-CHOP-type chemotherapy. ZEB1 and Slug expression correlated with adverse disease presentation. However, cytoplasmic Slug expression was linked to a favourable disease outcome, whereas nuclear expression of ZEB1 indicated an adverse outcome. Conclusions: This study shows that an EMT-like process occurs in lymphomas. Of the TFs investigated, ZEB1 seems to be the main one associated with adverse clinical presentation and clinical outcome. Surprisingly, Slug expression in cytoplasm was linked to a favourable prognosis. Further studies are needed to evaluate whether inhibition of ZEB1 could serve as a therapeutic target.
p53 mutations and high protein expression are associated with adverse prognosis in several lympho... more p53 mutations and high protein expression are associated with adverse prognosis in several lymphoma subtypes. Matrix metalloproteinase-9 (MMP-9) has also been found to correlate with poor survival in all lymphomas studied. The data concerning the clinical role of protein expression of p53 or gelatinases and their inhibitors in follicular lymphoma are rare. The purpose of this study was to evaluate the prognostic and clinical implications of the immunoreactive proteins p53, MMP-2, MMP-9, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and TIMP-2 in follicular lymphoma. The material consisted of 67 patients with primarily non-transformed follicular lymphoma. Diagnostic lymph node tissue sections of patients were stained by immunohistochemical method using specific monoclonal antibodies. p53 over-expression was detected in 8 (12%) out of 67 cases. p53 over-expression correlated with high grade (P = 0.011), bulky tumour (P = 0.031) and forthcoming transformation (P = 0.001). It also correlated with poor overall (P = 0.001) and cause-specific survival (P = 0.010) in multivariate analysis and had a strong inverse correlation with time to transformation (P < 0.001). MMP-2, MMP-9 and TIMP-2 expression correlated with high grade. MMP-9 positivity in centroblasts correlated with good chemotherapy response (P = 0.019), but it was not prognostic for survival. MMP-2, TIMP-1 or TIMP-2 did not associate with survival, either. In this study, p53 over-expression predicted both transformation to diffuse large B-cell lymphoma and poorer overall and cause-specific survival of patients with follicular lymphoma. Expression of gelatinases or their inhibitors did not have any significant correlations with prognosis, although MMP-9 predicted a good response to first-line chemotherapy.
Matrix metalloproteinases (MMPs) are involved in tumor growth and spreading. Here, we investigate... more Matrix metalloproteinases (MMPs) are involved in tumor growth and spreading. Here, we investigated the tumor immunoreactive protein of MMP-2, MMP-9 and TIMP-1 as well as the levels of circulating total TIMP-1 and MMP-2/TIMP-2-complex as prognostic factors in lung cancer patients. The material included 59 patients, 30 with a squamous cell carcinoma, 21 with an adenocarcinoma and eight with other histology.
Dendritic cells play an integral role in the normal physiological function of lymph nodes. They p... more Dendritic cells play an integral role in the normal physiological function of lymph nodes. They participate in the clonal expansion and evolution of B-cells [1] and induce specific immune responses [2]. In Hodgkin’s lymphoma, the existence of an intact dendritic cell reticulum has been shown to be a positive prognostic indicator in a retrospective Hodgkin’s lymphoma set treated mainly with radiotherapy [3]. The aim of the present study was to explore whether preservation of the denritic cell network could serve as a prognostic indicator also in Hodgkin’s lymphoma patients treated with modern treatment modalities. The series consisted of 63 adult patients (15 – 88 years old) with histologically proven Hodgkin’s lymphoma treated at the Department of Radiotherapy and Oncology, Oulu University Hospital, between January 1990 and December 1997. The patients were diagnosed and staged according to the routine lymphoma staging procedures. Thirty-five patients were treated with either chemotherapy or combined chemoand radiotherapy and 28 patients recieved radiotherapy alone. Paraffin sections were stained for cystatin A using a monoclonal anti-cystatin A antibody (commercially available from Sigma Chemical Co and from Alexis Biochemicals) diluted 1/800 and 1/1600 in PBS containing 1% bovine serum albumin according to methods described earlier [3]. Also sample evaluation and statistical methods followed the previous scheme. In the present study, using a monoclonal cystatin A antibody, we were unable to confirm earlier findings of the prognostic significance of preserved dendritic cell network in Hodgkin’s lymphoma in the whole material. However, when considering patients treated with radiation therapy alone a trend towards worse survival could be detected in patients with a disrupted dendritic cell reticulum, not falling far apart from previous studies. No patients with a preserved dendritic cell reticulum (8 patients) died of Hodgkin’s lymphoma compared to 5 of 20 with a disrupted dendritic cell reticulum. Alavaikko et al. have published a study of 139 Hodgkin’s lymphoma patients treated between the years 1963 and 1989 at our hospital and Tampere University Hospital, and they found a preserved dendritic cell network to be of marked prognostic relevance [3]. Our results are not in line with their findings. However, this new set of patients were all treated in the 1990’s. Between these 2 study periods, there have been remarkable changes in the diagnostic and treatment modalities of Hodgkin’s lymphoma, and survival has been steadily increasing. The most important changes have been the development and wide adoption of new effective chemotherapeutic combinations, such as ABVD and MOPP/ABVD, and the development of highdose treatment with stem cell support for patients with refractory or relapsing disease. These changes may have affected the prognostic importance of the different biological features of the disease. It could be anticipated that, at the time when large-field radiation therapy was the primary treatment modality, the significance of immune response to control the microscopic residual disease outside the treatment field would have been of a major prognostic significance. On the other hand, in patients treated with modern multi-agent chemotherapy regimens, the tumors chemosensitivity is probably a much more significant discriminating factor in prognosis. In fact, we saw a trend toward poorer survival in the patients
Diffuse large B-cell lymphoma (DLBCL) is an aggressive and potentially fatal disease. Prediction ... more Diffuse large B-cell lymphoma (DLBCL) is an aggressive and potentially fatal disease. Prediction of risk of relapse is based on clinical markers. There is a need for more accurate biomarkers to select patients for more aggressive first-line treatments. Peroxiredoxins (Prxs) are a family of potent antioxidant proteins. Their prognostic role in DLBCL is unknown. Altogether, 103 diagnostic biopsy samples from patients with DLBCL were immunohistochemically stained for Prxs I, II, III, V and VI. Strong Prx VI expression was associated with the presence of B-symptoms. There were no other significant associations with traditional risk factors. Five-year disease-specific survival was 68.6% in patients with high cytoplasmic Prx VI intensity vs 97.0% in those with low intensity. In multivariate analysis, high Prx VI expression (HR 12.846, 95% CI 1.722 to 95.807, p=0.013) was an independent risk factor of lymphoma-associated death not related to International Prognostic Index score (HR 2.514, 95% CI 1.040 to 6.073, p=0.041). High intensity of cytoplasmic Prx VI expression in pretreatment DLBCL samples predicts worse outcome in patients with DLBCL. Whether Prx VI is associated with chemoresistance, and therefore a poorer outcome, needs to be evaluated. If Prx VI is a predictive marker and it proves causality, it would be crucial to study Prx VI ability to become a target enzyme for treatment.
The molecular mechanisms underlying prostate carcinogenesis are poorly understood. Prostatic acid... more The molecular mechanisms underlying prostate carcinogenesis are poorly understood. Prostatic acid phosphatase (PAP), a prostatic epithelial secretion marker, has been linked to prostate cancer since the 1930's. However, the contribution of PAP to the disease remains controversial. We have previously cloned and described two isoforms of this protein, a secretory (sPAP) and a transmembrane type-I (TMPAP). The goal in this work was to understand the physiological function of TMPAP in the prostate. We conducted histological, ultra-structural and genome-wide analyses of the prostate of our PAP-deficient mouse model (PAP 2/2) with C57BL/6J background. The PAP 2/2 mouse prostate showed the development of slow-growing non-metastatic prostate adenocarcinoma. In order to find out the mechanism behind, we identified PAP-interacting proteins byyeast two-hybrid assays and a clear result was obtained for the interaction of PAP with snapin, a SNAREassociated protein which binds Snap25 facilitating the vesicular membrane fusion process. We confirmed this interaction by co-localization studies in TMPAP-transfected LNCaP cells (TMPAP/LNCaP cells) and in vivo FRET analyses in transient transfected LNCaP cells. The differential gene expression analyses revealed the dysregulation of the same genes known to be related to synaptic vesicular traffic. Both TMPAP and snapin were detected in isolated exosomes. Our results suggest that TMPAP is involved in endo-/exocytosis and disturbed vesicular traffic is a hallmark of prostate adenocarcinoma.
Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma with diverse outcomes. Concurrent... more Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma with diverse outcomes. Concurrent translocation of MYC and BCL-2 and/or BCL-6, and concurrent immunohistochemical (IHC) high expression of MYC and BCL-2, have been linked to unfavorable treatment responses. TP53-mutated DLBCL has also been linked to worse outcome. Our aim was to evaluate the aforementioned issues in a cohort of 155 patients uniformly treated with R-CHOP-like therapies. We performed direct sequencing of TP53 exons 5, 6, 7 and 8 as well as fluorescence in-situ hybridization (FISH) of MYC, BCL-2 and BCL-6, and IHC of MYC, BCL-2 and BCL-6. In multivariate analysis, TP53 mutations in L3 and loop-sheet helix (LSH) associated with a risk ratio (RR) of disease-specific survival (DSS) of 8.779 (p = 0.022) and a RR of disease-free survival (DFS) of 10.498 (p = 0.011). In IHC analysis BCL-2 overexpression was associated with inferior DFS (p = 0.002) and DSS (p = 0.002). DLBCL with BCL-2 and MYC overexpression conf...
Central nervous system (CNS) relapse occurs in around 5% of diffuse large B‐cell lymphoma (DLBCL)... more Central nervous system (CNS) relapse occurs in around 5% of diffuse large B‐cell lymphoma (DLBCL) cases. No biomarkers to identify high‐risk patients have been discovered. We evaluated the expression of lymphocyte‐guiding chemokine receptors in systemic and CNS lymphomas. Immunohistochemical staining for CXCR4, CXCR5, CCR7, CXCL12, and CXCL13 was performed on 89 tissue samples, including cases of primary central nervous system lymphoma (PCNSL), secondary CNS lymphoma (sCNSL), and systemic DLBCL. Also, 10 reactive lymph node samples were included. Immunoelectron microscopy was performed on two PCNSLs, one sCNSL, one systemic DLBCL, and one reactive lymph node samples, and staining was performed for CXCR4, CXCR5, CXCL12, and CXCL13. Chi‐square test was used to determine correlations between clinical parameters, diagnostic groups, and chemokine receptor expression. Strong nuclear CXCR4 positivity correlated with systemic DLBCL, whereas strong cytoplasmic CXCR5 positivity correlated wit...
Primary central nervous system lymphoma (PCNSL) is a rare brain tumour with a dismal prognosis. S... more Primary central nervous system lymphoma (PCNSL) is a rare brain tumour with a dismal prognosis. Several phase II studies with high-dose methotrexate-based regimens have shown promising early results, but in all hospital-based data published so far, the disease outcome is poor. We performed a hospital-based retrospective analysis to evaluate the long-term results of the Nordic type of Bonn chemotherapy regimen in PCNSL patients. The study included 54 patients with newly diagnosed PCNSL who received chemotherapy with curative intent as their first-line treatment. We found promising response rates, 76% of the patients achieving CR and 22% patients achieving PR, with corresponding two-year EFS 53% and OS 76%. However, with longer follow-up a constant pattern of relapses was observed with only one patient remaining in primary remission after 60 months. The finding suggests that basic biological differences exist between PCNSL and systemic diffuse large B-cell lymphoma and there is a need for consolidation or maintenance therapy after achieving a remission in patients with PCNSL.
Although oxidative stress plays an important role in the biology of solid malignant tumors, littl... more Although oxidative stress plays an important role in the biology of solid malignant tumors, little is known about oxidative stress in hematological malignancies. In this study, we evaluated the immunohistochemical expression and clinical correlations of oxidative stress markers and several essential antioxidant enzymes in B-cell lymphomas. Paraffin-embedded diagnostic tissue samples from 18 diffuse large B-cell lymphomas (DLBCL), 18 follicular lymphomas (FL), 19 Hodgkin lymphomas (HL), 7 chronic lymphocytic leukemias (CLL), 7 mantle cell lymphomas (MCL) and 7 mucosa-associated lymphoid tissue (MALT) lymphomas, together with samples from 6 reactive lymph nodes were stained for oxidative stress markers 8-hydroxydeoxyguanosine (8-OHdG) and nitrotyrosine and antioxidant enzymes manganese superoxide dismutase (MnSOD), thioredoxin (Trx) and γ-glutamyl cysteine synthetase (γ-GCS). There was increased 8-OHdG reactivity in DLBCL compared to more indolent lymphomas and reactive lymph nodes. Positivity for Trx was most intense in HL. In DLBCL, positivity for 8-OHdG and nitrotyrosine associated with shorter survival (p = 0.032 and p = 0.026, respectively). This study showed increasing expression of oxidative stress markers and antioxidant enzymes in a series of lymph node samples evolving from reactive lymph nodes to indolent and aggressive lymphomas. These markers seem to have strong prognostic value, but this has to be verified in larger studies.
Dendritic cells play an integral role in the normal physiological function of lymph nodes. They p... more Dendritic cells play an integral role in the normal physiological function of lymph nodes. They participate in the clonal expansion and evolution of B-cells [1] and induce specific immune responses [2]. In Hodgkin’s lymphoma, the existence of an intact dendritic cell reticulum has been shown to be a positive prognostic indicator in a retrospective Hodgkin’s lymphoma set treated mainly with radiotherapy [3]. The aim of the present study was to explore whether preservation of the denritic cell network could serve as a prognostic indicator also in Hodgkin’s lymphoma patients treated with modern treatment modalities. The series consisted of 63 adult patients (15 – 88 years old) with histologically proven Hodgkin’s lymphoma treated at the Department of Radiotherapy and Oncology, Oulu University Hospital, between January 1990 and December 1997. The patients were diagnosed and staged according to the routine lymphoma staging procedures. Thirty-five patients were treated with either chemotherapy or combined chemoand radiotherapy and 28 patients recieved radiotherapy alone. Paraffin sections were stained for cystatin A using a monoclonal anti-cystatin A antibody (commercially available from Sigma Chemical Co and from Alexis Biochemicals) diluted 1/800 and 1/1600 in PBS containing 1% bovine serum albumin according to methods described earlier [3]. Also sample evaluation and statistical methods followed the previous scheme. In the present study, using a monoclonal cystatin A antibody, we were unable to confirm earlier findings of the prognostic significance of preserved dendritic cell network in Hodgkin’s lymphoma in the whole material. However, when considering patients treated with radiation therapy alone a trend towards worse survival could be detected in patients with a disrupted dendritic cell reticulum, not falling far apart from previous studies. No patients with a preserved dendritic cell reticulum (8 patients) died of Hodgkin’s lymphoma compared to 5 of 20 with a disrupted dendritic cell reticulum. Alavaikko et al. have published a study of 139 Hodgkin’s lymphoma patients treated between the years 1963 and 1989 at our hospital and Tampere University Hospital, and they found a preserved dendritic cell network to be of marked prognostic relevance [3]. Our results are not in line with their findings. However, this new set of patients were all treated in the 1990’s. Between these 2 study periods, there have been remarkable changes in the diagnostic and treatment modalities of Hodgkin’s lymphoma, and survival has been steadily increasing. The most important changes have been the development and wide adoption of new effective chemotherapeutic combinations, such as ABVD and MOPP/ABVD, and the development of highdose treatment with stem cell support for patients with refractory or relapsing disease. These changes may have affected the prognostic importance of the different biological features of the disease. It could be anticipated that, at the time when large-field radiation therapy was the primary treatment modality, the significance of immune response to control the microscopic residual disease outside the treatment field would have been of a major prognostic significance. On the other hand, in patients treated with modern multi-agent chemotherapy regimens, the tumors chemosensitivity is probably a much more significant discriminating factor in prognosis. In fact, we saw a trend toward poorer survival in the patients
Hodgkin lymphoma treatments are largely based on the generation of reactive oxygen species, but i... more Hodgkin lymphoma treatments are largely based on the generation of reactive oxygen species, but increased expression of antioxidant enzymes may contribute to chemoresistance. The aims of this study were: to define the extent and prognostic value of oxidative stress marker and antioxidant enzyme expression in Hodgkin lymphomas; and to investigate a potential association between antioxidant enzymes and chemoresistance. We immunohistochemically assessed expression of peroxiredoxin (Prx) II, Prx III, Prx V, Prx VI, manganese superoxide dismutase (MnSOD), 8-hydroxydeoxyguanosine (8-OHdG) and nitrotyrosine in 99 cases of uniformly treated Hodgkin lymphoma. Localization of 8-OHdG was assessed using transmission electron microscopy, which demonstrated expression in the cytosol and mitochondria. 8-OHdG expression in Reed-Sternberg (RS) cells was associated with advanced stage (P = 0.006) and a lower International Prognostic Score (P = 0.004). Prx III expression in reactive cellular infiltrate was associated with advanced stage (P = 0.002) and B-symptoms (P = 0.0006). Strong cytoplasmic Prx V immunostaining was associated with a low rate of complete response to chemotherapy (P = 0.043). MnSOD immunostaining in RS cells was related to advanced stage (P = 0.031) and to poorer relapse-free survival (RFS) (P = 0.033). Low 8-OHdG expression in the nuclei of RS cells was a predictor of poorer RFS (P = 0.038). Both 8-OHdG and MnSOD were also significant RFS predictors in multivariate analysis. Our results suggest that significant oxidative stress exists in Hodgkin lymphomas, both in RS cells and in reactive cellular infiltrates. Mitochondrial antioxidant enzymes are induced in the most aggressive forms of the disease, and they may play some part in chemoresistance.
Biological roles and prognostic values of the epithelial-mesenchymal transition-mediating transcr... more Biological roles and prognostic values of the epithelial-mesenchymal transition-mediating transcription factors Twist, ZEB1 and Slug in diffuse large B-cell lymphoma Aims: To evaluate the biological roles and prognostic significance of the epithelial-mesenchymal transition (EMT)-mediating transcription factors (TFs) Twist, ZEB1 and Slug in patients with diffuse large B-cell lymphoma (DLBCL). EMT has been shown to enhance solid tumour metastasis, invasion, and proliferation. Methods and results: Expression of Twist, ZEB1 and Slug was evaluated immunohistochemically in eight samples from reactive lymphoid tissues and in diagnostic samples from 102 DLBCL patients treated with curative intent with R-CHOP-type chemotherapy. ZEB1 and Slug expression correlated with adverse disease presentation. However, cytoplasmic Slug expression was linked to a favourable disease outcome, whereas nuclear expression of ZEB1 indicated an adverse outcome. Conclusions: This study shows that an EMT-like process occurs in lymphomas. Of the TFs investigated, ZEB1 seems to be the main one associated with adverse clinical presentation and clinical outcome. Surprisingly, Slug expression in cytoplasm was linked to a favourable prognosis. Further studies are needed to evaluate whether inhibition of ZEB1 could serve as a therapeutic target.
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