| 1. |
- Andersson, Bengt-Åke
(författare)
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Circulating Biomarkers in Patients with Head and Neck Cancer and the Influence of Cigarette Smoking
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Head and neck cancer (HNC) is a collective name for heterogeneous tumors located in the head and neck regions for which smoking, alcohol and human papillomavirus (HPV) are documented risk factors. The survival of HNC patients has only improved marginally during the last decade. The most important prognostic factors are tumor size, local spread and distant metastases, tumor node metastasis (TNM) staging. Prognostic biomarkers are needed as a complement to TNM staging.The aim for this thesis was to investigate rapid and low cost blood based biomarkers which could indicate the risk of HNC, recurrence of the disease or the survival of HNC patients. Furthermore, the aim was to examine how cigarette smoking influences the levels of biomarkers.In paper I, a possible role of plasma cytokines or proteins associated with immune response or inflammation, as biomarkers for the survival of HNC patients was investigated. Higher levels of C-reactive protein (CRP) and tumor necrosis factor alpha (TNF-α) were detected in plasma of the patients compared with the levels in the controls. The elevated levels of these two biomarkers detected in patients were associated with decreased survival.In paper II, the influence of 45 single nucleotide polymorphisms (SNPs) located in 41 genes associated with cell cycle progression, cell death, DNA repair or immune response on cancer risk, tumor recurrence and survival in HNC patients were investigated. SNPs in immune response genes were associated with risk for HNC, an elevated risk for recurrence and a decreased survival in HNC patients.In paper III, the influence of cigarette smoking on levels of inflammatory cells, proteins or cytokines/chemokines, microRNAs (miRNAs) and SNPs was analysed in healthy smokers and non-smokers. Higher levels of total white blood cells (WBCs), neutrophils, monocytes, lymphocytes, neutrophil to lymphocyte ratio (NLR), CRP, monocyte chemoattractant protein- 1 (MCP-1) and interferon gamma (IFN-γ) were detected in smokers compared to non-smokers and indicate an inflammatory response. Also, a lower level of oncomiRNA miR-21was detected in smokers. This alteration, in combination with the elevated levels of IFN-γ in smokers could be a protective response to cigarette smoke. The higher levels of IFN-γ in smokers compared to non-smokers were however only detected in individuals with SNP rs2069705 genotype AG/GG. This indicates a genetic association of the levels of IFN-γ.In paper IV, the separate effects of cigarette smoking and HNC on inflammatory or immune biomarkers and the impact of high risk human papillomavirus, age and gender were investigated. Comparisons of circulating levels of WBCs and its subpopulations, plasma proteins or cytokines/chemokines between smoking and non-smoking patients, smoking and non-smoking controls and between the patient and control groups were analysed. Smoking had highest impact on elevated levels of WBCs, IFN-γ and MCP-1, and HNC had highest impact on elevated levels of neutrophils, monocytes, NLR, CRP, macrophage inflammatory protein 1 beta and TNF-α.In conclusion, host immune response associated parameters could be suitable as biomarkers for the risk of HNC, risk of recurrence or in predicting survival of HNC patients. This thesis show that HNC are associated with systemic inflammatory response and upregulated CRP and TNF-α is related to shorter survival in HNC patients. Additionally, SNPs in immune response genes such as rs1800629 in the TNF-α gene indicates a risk for HNC or an elevated risk for recurrence and a decreased survival in HNC patients. These rapid and low cost blood based biomarkers could be used in combination or as a supplement to established biomarkers in the clinic for a more personalized treatment modality.
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| 2. |
- Lindahl, Gabriel, 1971-
(författare)
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The effects of flaxseed and tamoxifen on the inflammatory microenvironment in normal breast tissue and in breast cancer
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Breast cancer is the most common cancer among women worldwide today. Nearly 9000 women are diagnosed with breast cancer in Sweden yearly and despite advantages in diagnostics and treatments approximately 1400 women still die from their disease every year. Breast cancer has a diverse etiology and hormonal factors and life-style factors contribute to an increased breast cancer risk. High mammographic density is also considered a risk factor but the underlying mechanisms are not fully understood. Inflammation is associated with poor survival in several malignancies and is considered a hallmark of cancer. There is evidence indicating that increased inflammation is associated with dense breast tissue and may contribute to an increased risk of breast cancer in these patients.There is an urgent need to find risk reduction strategies in breast cancer prevention. Several studies have shown that antiestrogens significantly reduce breast cancer incidence in women with high risk of developing breast cancer and can be used for chemoprevention. These drugs may have potentially severe side effects and other strategies are needed. Dietary interventions may influence breast cancer risk without any major side effects. Studies indicate that dietary phytoestrogens may reduce breast cancer risk. The most common phytoestrogens in Western populations are lignans, mainly found in flaxseed, but results from several studies with lignans for breast cancer prevention have been inconsistent.In this thesis we investigated the effects of tamoxifen and flaxseed on inflammatory mediators in normal breast tissue and in breast cancer. We used the microdialysis technique to sample proteins from the extracellular space in vivo. This technique gives us the opportunity to study proteins in their bioactive compartment in situ and to study changes in protein levels at different time points without affecting the tissue of interest. We also used experimental models and cell cultures to study tumor growth of human breast cancer xenografts, cancer cell proliferation and angiogenesis.In paper I, we investigated whether tamoxifen, flaxseed, enterolactone or genestein reduced growth of human breast cancer xenografts and their association with pro-inflammatory cytokine interleukin 1β (IL-1β) and its antagonist interleukin 1 receptor antagonist (IL-1Ra). In paper II, we investigated whether tamoxifen and flaxseed exerted similar effects on inflammatory mediators in normal breast tissue in vivo. In paper III, we investigated whether osteopontin (OPN), a pro-inflammatory cytokine, was associated with dense breast tissue and breast cancer and if tamoxifen and flaxseed could alter OPN levels in normal breast tissue in vivo. We also investigated the correlation between OPN and inflammatory mediators in normal breast tissue and in breast cancer in vivo. In conclusion, we showed that tamoxifen and flaxseed affected breast cancer growth in an experimental model and may exert an anti-inflammatory effect in breast cancer and normal breast tissue by increasing the IL-1Ra/IL-1β ratio in vivo. We showed that dense breast tissue and breast cancer were associated with increased levels of OPN. Circulating estrogen did not correlate to OPN and tamoxifen and flaxseed did not affect OPN levels suggesting an estrogen independent regulation of OPN in vivo. These finding contributes to our understanding of how tamoxifen and flaxseed affects inflammation and the role of inflammation in the pathogenesis of breast cancer.
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