| 1. |
- Robinson, David, 1968-
(författare)
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Prediction of survival in prostate cancer : aspects on localised, locally advanced and metastatic disease
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background and aims: The clinical course of prostate cancer is highly variable and difficult to predict.Stage at presentation, grade and PSA at diagnosis are traditionally used to predict outcome. The aimof this thesis was to identify strategies for improved survival prediction in men with prostate cancer.The way in which prostate cancer affects a population based‐cohort and how routinely measuredvariables can be used to predict survival in an intermediate to long follow‐up period were explored.From this large cohort we separately evaluated how survival can be predicted in men with incidentalcarcinoma (T1a and b) and locally advanced disease (lymph node‐ positive). Immunohistochemistrywas added to routinely measured variables in the subgroup of men with incidental carcinoma.Furthermore, we assessed how the outcome of metastatic disease may be predicted from informationavailable at diagnosis, and during the first six months after treatment. Finally we predicted survivalfor men with metastatic hormone‐refractory prostate cancer (HRPC).Material and methods: From the Swedish South‐East Region Prostate Cancer Register data on 8887men were studied and the impact of tumour grade, serum PSA concentration, TNM classification andtreatment was studied in relation to survival.Furthermore, an evaluation of the disease‐specific mortality of conservatively managed incidentalcarcinoma in relation to T‐category, Gleason score, p53, Ki‐67, Chromogranin A and serotonin wasmade. From the same register we studied whether common predictive factors such as serum‐PSA, Tcategoryand biopsy tumour grade could be used to better assess the prognosis of men with nodepositiveprostate cancer. Using data from the clinical trial SPCG‐5 we studied the possibility of serialmeasurements of PSA and ALP being to predict survival early in the course of hormone‐treatedmetastatic prostate cancer. From the same trial, we also assessed the value of PSA kinetics inpredicting survival and related this to baseline variables in men with metastatic HRPC.Results: In the South–East Region, where screening was seldom done the median age at diagnosisand death was 75 and 80 years respectively, and 12% were diagnosed before the age of 65 years. Hightumour grade, high serum PSA and high T category were associated with poor outcome. The projected 15‐year disease‐specific survival rate was 44% for the whole population. In total, 18% ofpatients had metastases at diagnosis and their median survival was 2.5 years.In the cohort of men with incidental carcinoma, 17% died of prostate cancer. Of 86 patients withGleason score ≤5, three died of prostate cancer. Independent predictors of disease‐specific mortality inmultivariate analysis were category T1b prostate cancer, Gleason score >5 and high immunoreactivityof Ki‐67. Men with lymph‐node positive disease have a median cancer‐specific survival of 8 years.Preoperatively known factors such as PSA, T‐category, age, mode of treatment, failed to predictoutcome, but there was a weak, not statistically significant difference in cancer‐specific survival inrelation to tumour grade.Initial ALP, and ALP and PSA after 6 months of treatment were the serum markers that provided thebest prognostic information about the long‐term outcome of metastatic prostate cancer. In men withHRPC, PSA velocity alone gave a better prediction of survival than all other PSA kinetic variables.Conclusion: In an almost unscreened population, prostate cancer is the elderly mans disease but themortality is high. Ki‐67 may be of value in addition to stage and Gleason score for predicting theprognosis in men with incidental carcinoma.The impact of lymph node metastases on survival overrides all other commonly used prognosticfactors.By following ALP and PSA for 6 months it is possible to predict outcome in metastatic prostate cancer.This gives a much better prediction than baseline PSA and helps to select men with a poor prognosis.By combining PSAV with the variables available at baseline, a better ground for treatment decisionmakingin men with HRPC is achieved.
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| 2. |
- Andersson, Patiyan, 1978-
(författare)
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Molecular Genetic Studies on Prostate and Penile Cancer
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis is comprised of two parts. In the first part we study the influence of four frequently disputed genes on the susceptibility for developing prostate cancer, and in the second part we attempt to establish a basic understanding of the molecular genetic events in penile cancer.In a prostate cancer cohort we have investigated the relation of prostate cancer risk and single nucleotide polymorphisms (SNPs) in four different genes coding for the androgen receptor (AR), the vitamin D receptor (VDR), insulin (INS) and insulin receptor substrate 1 (IRS1). Despite strong biological indications of an involvement of these genes in prostate carcinogenesis, the results from different studies are contradictory and inconclusive.The action of the AR varies between individuals in part owing to a repetitive CAG sequence (polyglutamine) in the first exon of the AR gene. The results presented in this thesis show that in our cohort of prostate cancer patients the average number of repeats is 20.1, which is significantly (p<0.001) fewer repeats compared to healthy control individuals, where the average is 22.5 repeats. We find a 4.94 fold (p=0.00003) increased risk of developing prostate cancer associated with having short repeat lengths (≤19 repeats), compared with long repeats (≥23 repeats). In paper I we also study the TaqI polymorphism in the VDR gene, and find that it does not modify the risk of prostate cancer.In the INS gene we study the +1127 PstI polymorphism and find no overall effect on the risk of prostate cancer. However, we do find that the CC genotype is associated with low grade disease defined as having a Gleason score ≤6 (OR=1.46; p=0.018). In the IRS1 gene we study the G972R polymorphism and observe that the R allele is significantly associated with a 2.44 fold increased prostate cancer risk (p=0.010).The knowledge of molecular genetic events in penile cancer is very scarce and to date very few genes have been identified to be involved in penile carcinogenesis. We chose therefore to analyse the penile cancer samples using genome-wide high-density SNP arrays. We find major regions of frequent copy number gain in chromosome arms 3q, 5p and 8q, and slightly less frequent in 1p, 16q and 20q. The chromosomal regions of most frequent copy number losses are 3p, 4q, 11p and 13q. We suggest four candidate genes residing in these areas, the PIK3CA gene (3q26.32), the hTERT gene (5p15.33), the MYC gene (8q24.21) and the FHIT gene (3p14.2).The mutational status of the PIK3CA and PTEN genes in the PI3K/AKT pathway and the HRAS, KRAS, NRAS and BRAF genes in the RAS/MAPK pathway was assessed in the penile cancer samples. We find the PIK3CA, HRAS and KRAS genes to be mutated in 29%, 7% and 3% of the cases, respectively. All mutations are mutually exclusive. In total the PI3K/AKT and RAS/MAPK pathways were found to be activated through mutation or amplification in 64% of the cases, indicating the significance of these pathways in the aetiology of penile cancer.
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| 3. |
- Sjölund, Jonas
(författare)
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Notch Signaling in Neuroblastoma and Renal Cell Carcinoma
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Notch signaling pathway governs cell functions essential for normal development and organogenesis. Aberrant Notch signaling has been implicated in tumorigenesis by perturbing control of proliferation, differentiation, apoptosis, migration and angiogenesis. Neuroblastoma is an embryonal tumor derived from cells of the sympathetic nervous system, arrested at an immature stage of differentiation. Notch signaling is thought to play an important role during the development of the sympathetic nervous system, and prior studies have indicated that dysregulated Notch signaling might be associated with the perturbed differentiation that characterize neuroblastoma cells. Here we show that the histone deacetylase inhibitor valproic acid induced differentiation of neuroblastoma cells, in conjunction with activation of Notch-1 signaling. In addition, we also noted that the expression of the Notch target HES-1 was primarily regulated by ERK-MAP kinase signaling in a neuroblastoma cell line. Clear cell renal cell carcinoma (CCRCC) is characterized by activation of the hypoxia inducible factor (HIF) pathway due to functional loss of the von Hippel-Lindau tumor suppressor gene. However, cooperating oncogenic events parallel to the HIF pathway remains poorly described. Our results presented here imply a growth-promoting role for Notch signaling in CCRCC cells, seemingly independent of HIF-regulated cellular events. Treatment of nude mice bearing CCRCC xenografts, with daily injections of a Notch inhibitor (γ-secretase inhibitor) in cycles of 3 days followed by 4 days without treatment, retarded tumor growth and minimized the adverse effects commonly associated with γ-secretase inhibition. In addition, analysis of primary CCRCC samples revealed that Notch-1 and Jagged-1 were expressed at significantly higher levels compared to normal kidney tissue samples. Finally, we found that inhibition of Notch signaling decreased the migratory potential of CCRCC cells. This effect might be linked to a cross-talk between Notch and TGF-β signaling in CCRCC cells.
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| 4. |
- Thellenberg Karlsson, Camilla, 1972-
(författare)
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Prostate cancer : epidemiological studies of risk factors
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In spite of the fact that prostate cancer is the most common male cancer in both Sweden and many other countries in the developed world, little is known of risk factors and predisposing conditions. The only well recognized risk factors are age, race and familial aggregation. More knowledge about risk factors could lead to better preventive measures together with better treatments. One way to evaluate this is to study second primary cancers; the connection between two different cancers can give valuable insight in etiology or clues to shared risk factors. This thesis aims at evaluating risk factors for prostate cancer. We constructed a cohort of 135,713 men diagnosed with prostate cancer and reported to the Swedish Cancer Registry 1958-1996. The cohort was followed for second primary cancers and a doubled risk of male breast cancer was found. We also noted increased risks for small intestine cancers and melanoma. As a follow-up on the increased risk of male breast cancer, we performed a nested case – control study. Included cases were men with first prostate and then breast cancer (n = 41) matched to men with only prostate cancer (n =81). For these men, we collected medical records and extracted data regarding treatment. Furthermore, all men diagnosed with both prostate and breast cancer irrespective which came first (n = 83) were used as probands. To both these sets of cases with breast and prostate cancer, we identified first degree relatives and grandchildren from parish offices throughout Sweden. Linking to the Cancer Registry retrieved all cancer diagnoses amongst relatives. Results from this study show a relation between estrogen treatment of prostate cancer and the risk of developing breast cancer. We also found that a small part of the cases with both cancers appeared in families with inheritance patterns possibly attributed to BRCA2. As estrogen treatment seemed involved in increased risk of breast cancer after prostate cancer, we wanted to investigate the newly discovered Estrogen receptor β and the relation to prostate cancer risk. Previous reports have shown that ERβ acts as a negative regulator of proliferation. ERβ expression occurs mainly in prostatic epithelial cells and the expression gradually diminishes when cancer develops and aggravates. We used a single nucleotide polymorphism (SNP) association study approach to evaluate genetic variation in ERβ as a risk factor for prostate cancer. One SNP, located in the promoter region associated with a small increased risk of prostate cancer whereas variation in the rest of the gene did not. In the last paper, we investigated trans-urethral resection (TURP) of the prostate due to benign prostate hyperplasia (BPH) as a risk factor for later development of prostate cancer. Evidence has gathered that both BPH and prostate cancer are associated to inflammation. By comparing incidence and mortality in a cohort of 7,901 men with the general population there appeared to be an increased risk of prostate cancer but decreased mortality. Analyzing this increased risk further, we conducted a nested case - control study with men extracted from the cohort. Cases had a TURP and later developed prostate cancer and controls just had a TURP. We then evaluated the specimens from TURP regarding extent of inflammation, degree of androgen receptor down regulation and expression of p53, all factors previous associated with prostate cancer. None of these parameters differed between cases and controls and they can therefore not explain the increased risk. Decreased mortality but increased risk might be explained by surveillance bias, which means more medical attention to these patients, resulting in diagnosing clinically non-significant cancers. In summary, our results show a doubled risk of male breast cancer following prostate cancer. A risk that can be attributed to the use of estrogen to treat prostate cancer or to some extent a possible mutation in BRCA2. We also propose that a SNP change in the ERβ promoter confer a small increased risk of prostate cancer. A small risk elevation of prostate cancer following TURP most probable could depend on surveillance bias.
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| 5. |
- Gao, Jingfang, 1966-
(författare)
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Molecular and Biological Characteristics of Stroma and Tumor Cells in Colorectal Cancer
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Carcinogenesis is a progressive process involving multiple genetic alterations in tumor cells and complex interactions in the tumor-host microenvironment. To better understand the contribution of molecular alterations in tumor cells and stromal variables to the development of colorectal cancer (CRC) and identify prognostic factors, in this study we examined the clinicopathological and biological significance of stromal variables, including particularly interesting new cysteine-histidine rich protein (PINCH), inflammatory infiltration, angiogenesis and lymphangiogenesis, as well as hRAD50/hMRE11/hNBS1 proteins and hRAD50 mutation in tumor cell in CRC.PINCH protein expression in the stroma was increased from normal mucosa to primary tumors and further to lymph node metastases. In particular, PINCH expression was most intense at the tumor invasive margin, which was related to low inflammatory infiltration and independently related to an unfavorable prognosis. Low inflammatory infiltration at the tumor invasive margin was related to advanced tumor stage, worse differentiation and microsatellite instability (MSI). Further, it was independently related to an unfavorable prognosis. Increased blood and lymphatic vessel density was observed in the primary tumors compared with the corresponding normal mucosa. However, neither angiogenesis nor lymphangiogenesis was associated with tumor stage and patients’ survival. Moreover, PINCH was present in a proportion of endothelial cells of the tumor vasculature, and PINCH expression in tumor-associated stroma was positively related to blood vessel density.In primary tumor cells of CRC, strong expression of hRAD50, hMRE11 or hNBS1 was related to microsatellite stability (MSS). A high percentage of hMRE11 expression was associated with less local recurrence and high apoptotic activity. Further, we observed that the expression of hRAD50, hMRE11 or hNBS1 among normal mucosa, primary tumors and metastases in MSS CRC differed from that in MSI CRC. In MSS CRC, the expression intensity of hRAD50, hMRE11 and hNBS1 was consistently increased with respect to normal mucosa, but there was no difference between the primary tumors and metastases. In the primary MSS tumors, the expression of individual or combination of hRAD50/hMRE11/hNBS1 was associated with a favorable prognosis in the same series of the CRCs. Moreover, strong/high hRAD50 in MSS primary tumors was related to earlier tumor stage, better differentiation and high inflammatory infiltration, whereas strong hNBS1 expression tended to be independently related to a favorable prognosis in MSS CRC with earlier tumor stage. However, in MSI CRC, there were neither differences in the expression of hRAD50/hMRE11/hNBS1 among normal mucosa, primary tumors and metastases, nor any association of the protein expressions with clinicopathological variables. On the other hand, frameshift mutations of (A)9 at coding region of hRAD50 were only found in MSI CRC.Our study indicates that 1) PINCH is likely a regulator of angiogenesis, and PINCH expression at the tumor invasive margin is an independent prognostic indicator in CRC. 2) Inflammatory infiltration at the tumor invasive margin is also an independent prognostic indicator in CRC. The lack of association between high inflammatory infiltration and MSI may help to explain the non-association of MSI with survival in CRC patients. 3) Angiogenesis and lymphangiogenesis occur in the early stage of CRC development, but do not associate with CRC progression and patients’ prognosis. 4) hRAD50/hMRE11/hNBS1 may act dependently and independently, playing different roles in MSS and MSI CRC development. In MSS CRC, the strong expression of the three proteins, associated with a favorable prognosis, may present the cellular response against tumor progression. Expression of hNBS1 may be a prognostic indicator for MSS CRC patients in the earlier tumor stage. In MSI CRC, the frameshift mutations at the coding region of hRAD50 may contribute to tumor development.
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| 6. |
- Wallin, Åsa, 1976-
(författare)
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Molecular Studies of Irradiation and SN-38 on Colorectal Cancer
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Colorectal cancer (CRC) is one of most common cancer diseases worldwide. In Swedenapproximately 5,000 new cases of CRC are generated each year, which makes it the thirdmost common cancer disease among both men and women. The past decades ofimproved treatment strategies have considerably increased the five-year survival for CRCpatients. However more could be achieved in this area, in particular for metastatic CRC,which is the cause of most CRC-related deaths. Therefore it is important to study thebiological response to certain treatments induced in CRC to find valuable predictiveand/or prognostic factors to select patients for better suited treatments.The aim of this thesis was to gain insight into the molecular changes that occurfollowing irradiation or treatment with SN-38 in rectal cancer patients or colon cancercell lines by studying the RNA expression, protein expression, DNA cell cycledistribution and apoptotic response. The expression of phosphatase of regenerating liver(PRL) proteins was investigated in rectal cancers from 125 patients included in arandomized clinical trial of preoperative radiotherapy (RT). Increased expression of PRLswas seen at the invasive margin of primary and metastatic cancers compared with theinner area of the tumors. Moreover, strong PRL staining at the invasive margin correlatedto distant recurrence and worse survival of patients in the RT group but not in non-RTgroup (Paper I). Radiosensitivity was studied by treating KM12C, KM12SM andKM12L4a colon cancer cell lines with radiation. KM12C is of low metastatic naturecompared with the highly metastatic KM12SM and KM12L4a. Upregulation of ΔNp73and PRL-3 might contribute to the radioresistant phenotype in KM12C. In contrast,KM12L4a shows a high frequency of apoptosis and lack of upregulation of ΔNp73, PRL-3 and survivin, which might explain its radiosensitive phenotype (Paper II). KM12C,KM12SM and KM12L4a were treated with SN-38 which inhibits topoisomerase 1 (topo-1). The results show that SN-38 induces G2/S arrest and possess the capacity to triggerapoptosis in the three cell lines (Paper III). To further elucidate SN-38 effect on these celllines, the gene expression profile following SN-38 treatment was studied. Oligonucleotidearrays consisting of ~27,000 spots were hybridized with sample and reference cDNA.Both unsupervised and supervised hierarchical clustering analysis, and functional analysiswere performed. Supervised hierarchical clustering gives a strong signal of 1453discriminated genes, the vast majority being upregulated. Both upregulated anddownregulated genes point toward a favorable impact of SN-38 regarding the apoptoticpathways. For example RhoB and Bax are upregulated together with downregulation ofKras and survivin, which promotes apoptosis (Paper IV).In conclusion, PRLs may be valuable biomarkers for RT resistance, predicting apoor prognosis in rectal cancer patients. Targeting radio-resistance factors, such asΔNp73 and survivin may contribute to an increased sensitivity to RT. SN-38 affects cellproliferation and apoptosis.
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| 7. |
- Karlsson, Anneli, 1973-
(författare)
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Genetic Alterations in Lymphoma : with Focus on the Ikaros, NOTCH1 and BCL11B Genes
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cell proliferation is a process that is strictly regulated by a large number of proteins. An alteration in one of the encoding genes inserts an error into the regulative protein, which may result in uncontrolled cell growth and eventually tumor formation. Lymphoma is a cancer type originating in the lymphocytes, which are part of the body’s immune defence. In the present thesis, Znfn1a1, Notch1 and Bcl11b were studied; all involved in the differentiation of T lymphocytes. The three genes are located in chromosomal regions that have previously shown frequent loss of heterozygosity in tumor DNA.Ikaros is a protein involved in the early differentiation of T lymphocytes. In this thesis, mutation analysis of the Znfn1a1 gene in chemically induced murine lymphomas revealed point mutations and homozygous deletions in 13 % of the tumors. All of the detected deletions lead to amino acid substitutions or abrogation of the functional domains in the Ikaros protein. Our results support the role of Ikaros as a potential tumor suppressor in a subset of tumors.Notch1 is a protein involved in many differentiation processes in the body. In lymphocytes, Notch1 drives the differentiation towards a T-cell fate and activating alterations in the Notch1 gene have been suggested to be involved in T-cell lymphoma. We identified activating mutations in Notch1 in 39 % of the chemically induced murine lymphomas, supporting the involvement of activating Notch1 mutations in the development of T-cell lymphoma.Bcl11b has been suggested to be involved in the early T-cell specification, and mutations in the Bcl11b gene has been identified in T-cell lymphoma. In this thesis, point mutations and deletions were detected in the DNA-binding zinc finger regions of Bcl11b in 15 % of the chemically induced lymphomas in C57Bl/6×C3H/HeJ F1 mice. A mutational hotspot was identified, where four of the tumors carried the same mutation. Three of the identified alterations, including the hotspot mutation in Bcl11b, increased cell proliferation when introduced in a cell without endogenous Bcl11b, whereas cell proliferation was suppressed by wild-type Bcl11b in the same cell line. Mutations in Bcl11b may therefore be an important contributing factor to lymphomagenesis in a subset of tumors.A germ line point mutation was identified in BCL11B in one of 33 human B-cell lymphoma patients. Expression of BCL11B in infiltrating T cells was significantly lower in aggressive compared to indolent lymphomas, suggesting that the infiltrating T cells may affect the B-cell lymphomas.
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| 8. |
- Lindquist, David
(författare)
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Studies on the occurrence and effects of human papillomavirus in tumors of the head and neck
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The presence of human papillomavirus (HPV) in squamous cell carcinoma of the head and neck (HNSCC) was first reported in 1985. Since then, this association has been studied intensively and today there is substantial evidence for HPV as a causative agent and positive prognostic factor for clinical outcome in tonsillar cancer, but the association to other HNSCC is still unclear. The aim of this thesis was first to examine the presence of HPV in tongue cancer and to study its possible influence on disease outcome. Thereafter, the association between HPV and cdk inhibitor p16INK4a expression and a possible correlation to response to radiotherapy (RT) and survival was studied. A third aim of this thesis was to investigate if HPV is a potential risk factor for the increase in incidence of tonsillar cancer that has been observed in Sweden. Furthermore, presence of HPV, viral load and expression of the viral oncogenes E6 and E7 in tonsillar cancer was investigated and correlated to clinical outcome. In tongue cancer, HPV DNA detected by PCR was more commonly found in base of tongue cancer (40%) as compared to mobile tongue cancer (2.4%), and was a positive prognostic factor for survival in patients with base of tongue cancer. This finding indicates that HPV might not only be involved in tonsillar cancer, but also in base of tongue cancer, which has a similar histology and is also a part of oropharynx. In tonsillar cancer there was a strong correlation between a high expression of p16INK4a detected by immunohistochemistry (IHC) and presence of HPV detected by PCR. However, only high expression of p16INK4a, and not the presence of HPV, was shown to be a predictive factor for complete response to RT in tonsillar cancer. Nevertheless, both p16INK4a and HPV were positive predictive factors for clinical outcome. The incidence of tonsillar cancer and presence of HPV was studied in the Stockholm area during 1970-2002. HPV was detected by PCR in 49% of the patient samples and 87% of these were positive for HPV-16. The frequency of HPV positive tonsillar cancer increased 2.9-fold from 1970 to 2002 and during the same time period a parallel 2.8-fold increase in the incidence of tonsillar cancer was observed. These results strongly support HPV as a risk factor for the increase in incidence of tonsillar cancer. In the tonsillar cancer patients above, the finding of HPV as a positive prognostic factor in tonsillar cancer for clinical outcome was confirmed. In addition, HPV viral load and expression of the viral oncogenes E6 and E7 was analyzed with real time quantitative PCR and reverse transcriptase PCR in the HPV-16 positive tonsillar cancer samples. In most HPV-16 positive tumors, expression of E6 and E7 was ascertained. However, in contrast to earlier studies a high viral load was not correlated to survival. The findings of an increase in incidence of tonsillar cancer and a parallel increase in frequency of HPV positive tumors, a better disease specific survival, and the expression of viral oncogenes strongly support previous findings that HPV positive tonsillar cancer should be considered a different disease entity. If the now available prophylactic vaccines are included in the childhood vaccination program for girls, the possible effects on HPV positive tonsillar cancer should be discussed, since most patients with HPV positive tonsillar cancer are men.
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| 9. |
- Magnusson, Cecilia
(författare)
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Anti-Tumor Effects of CysLT2R in Epithelial Cancer
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The pro-inflammatory cysteinyl leukotrienes (cysLTs) are implicated in several pathological disorders, such as asthma and inflammatory diseases. The well-established connection between chronic inflammation and cancer implicates inflammatory mediators in cancer progression. It is therefore of interest to examine the effects of the CysLTs in cancer. The biological effects of CysLTs are mediated through two G-protein coupled receptors (GPCRs) denoted CysLT1R, which is the high affinity receptor for LTD4 and CysLT2R, which has lower but equal affinities for LTD4 and LTC4. Signaling through CysLT1R has been associated with increased cell proliferation, migration and survival. In this context we wanted to elucidate the role of CysLT2R in regard to cancer. In this thesis I show that the cellular localization patterns of CysLT1R and CysLT2R differ. Even though CysLT1R can be found at the nuclear membrane, CysLT2R is more pronouncedly expressed here in both colon and breast tumor cells, which is quite unusual for GPCRs. Moreover, we observed that CysLT2R was down-regulated in colon cancer and that more aggressive tumors expressed less of the receptor. In addition, LTC4, the major ligand for CysLT2R, mediated increased differentiation of the colon cancer cell line Caco-2. Interestingly, CysLT2R expression is induced by the anti-tumorigenic interferon a, whereas the mitogen inducer epidermal growth factor, suppresses the expression of CysLT2R. Furthermore, in breast cancer patients, high expression of CysLT2R predicts good five-year-survival, whereas high expression of CysLT1R mediates a poor prognosis. In addition, over-expression of CysLT2R suppressed the migratory capability of both breast epithelial and breast cancer cells in vitro. A selective CysLT2R inhibitor could block this effect. These results combined indicate that CysLT2R has a protective role against tumor progression.
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| 10. |
- Nilsson, Cathrine, 1978-
(författare)
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Impact of Lysosomal Function in Cancer and Apoptosis
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lysosomes, the recycling units of the cell, participate in the signaling pathway to apoptosis, which has stimulated the search for anti-cancer drugs targeting the lysosomal compartment. Lysosomes are, however, often altered in cancer cells. The aim of this thesis was to investigate the involvement of lysosomes during apoptosis in normal and cancer cells. We developed and used flow cytometric methods to measure cytosolic and lysosomal pH in cells. The cytosolic pH of U937 cells decreased, in a caspase-independent way, by 1.4 pH-units during apoptosis. Concomitantly, the lysosomal pH increased from 4.3 to 5.2, suggesting that proton release from lysosomes might be responsible for cytosolic acidification. When studying the lysosomal pH of head and neck squamous cell carcinoma (HNSCC) cell lines and normal oral keratinocytes (NOKs), the pH was significantly increased in three of five HNSCC cell lines, as compared to NOKs. Moreover, high lysosomal pH correlated to low expression of the B subunit of the vacuolar V0/V1-ATPase, a necessary component of the proton pump responsible for lysosomal acidification, and to reduced intrinsic cisplatin sensitivity. Cisplatin-induced apoptosis was, at least partly, dependent on lysosomal cathepsins. When investigating the colony formation ability of the two HNSCC cell lines LK0412 and SqCC/Y1, both were found to give rise to holoclones, indicating the presence of cells with cancer stem cell properties. Holoclone cells from the LK0412 cell line were less sensitive to cisplatin compared to more differentiated paraclone cells. Moreover, we detected differences in intracellular localization of the lysosomal compartment and expression of cathepsins between holo- and paraclone cells.This thesis shows that changes found in the lysosomal compartment of cancer cells, such as alteration of lysosomal pH, might influence the outcome of a drug treatment. In addition, differences in drug sensitivity between subpopulations of tumor cells may affect the outcome of an anticancer therapy.
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