Les cellules cancéreuses du sein se disséminent du site primaire aux organes secondaires, où elles restent dormantes pendant des mois, voire des années. Cette période de dormance se traduit par une latence clinique entre la résection chirurgicale des tumeurs mammaires primitives et le diagnostic d'une rechute métastatique chez environ 30 % des patientes atteintes d'un cancer du sein. Les mécanismes de survie et de croissance ultérieure de ces cellules tumorales disséminées (CTD) dormantes restent largement inconnus, ce qui entrave la prise en charge clinique des patientes concernés. Des facteurs intrinsèques et extrinsèques dictent le destin et le comportement des DTC dans les organes secondaires. Notre travail dans les chapitres deux et trois visait à révéler les gènes et les voies de signalisation contribuant au devenir du DTC en ce qui concerne les deux catégories de facteurs. Dans le chapitre deux, nous avons exploité les sous-lignées de cancer du sein murin 4T07 et 4T1 qui modélisent les deux destins de rester dormant ou de se transformer en métastases visibles, respectivement, après dissémination spontanée à partir de la tumeur mammaire primaire. Nous avons appliqué un pipeline de criblage CRISPR à l'échelle du génome pour explorer les dépendances génétiques différentielles des deux lignées, c’est à dire leur réseau de signalisation intrinsèquement différent. En comparaison avec les cellules sujettes à la dormance, les cellules métastatiques démontrent une activité PI3K de classe I élevée. Contre-intuitivement, les cellules sujettes à la dormance affichent une activité mTORC1 plus élevée qui pourrait être attribuée à un positionnement lysosomal périphérique constant. Le blocage de ce positionnement périphérique a réduit la charge des DTC dans les poumons et l'incidence des métastases visibles, ce qui suggère qu'il pourrait s'agir d'un mécanisme de survie médicamenteux pour les DTC du sein. Dans le chapitre trois, nous avons effectué un criblage CRISPR in vivo à l'échelle du génome dans des cellules sujettes à la dormance, ce qui a mené à l’identification du gène non caractérisé Mob3c comme un régulateur potentiel de la dormance. Le niveau d'expression de Mob3c dans les modèles de dormance par rapport à ses homologues prolifératifs a soutenu la prédiction du criblage selon laquelle Mob3c pourrait être un suppresseur de métastases. Des cribles basés sur la protéomique et des tests d'interactions protéine-protéine ont suggéré que MOB3C interagit avec le complexe endonucléase RNase P, qui catalyse différentes fonctions cellulaires essentielles, y compris la maturation de l'ARNt. Les analyses cliniques axées sur les rechutes métastatiques (c'est-à-dire la survie sans métastases à distance et sans progression) chez les patientes atteintes d'un cancer du sein ont validé les résultats précliniques décrits dans les deux chapitres, soutenant une signification et un impact potentiels des connaissances moléculaires révélées. / Breast cancer cells disseminate from the primary site to secondary organs, where they remain dormant for months to years. This dormancy period is reflected in a clinical latency between the surgical resection of the primary breast tumors and diagnosing a metastatic relapse in about 30% of breast cancer patients. Mechanisms of survival and subsequent outgrowth of these dormant disseminated tumor cells (DTCs) remain largely unknown, hence hindering clinical management of affected patients. Intrinsic and extrinsic factors dictate the fate and behavior of DTCs in secondary organs. Our work in chapters two and three aimed at revealing genes and pathways contributing to the DTC fate with respect to the two categories of factors. In chapter two, we leveraged the 4T07 and 4T1 murine breast cancer sublines that model the two fates of either remaining dormant or outgrowing into visible metastases, respectively, after spontaneous dissemination from the primary mammary tumor. We applied a genome wide CRISPR screening pipeline to explore the differential genetic dependencies of the two lines, hence their intrinsically different signaling wiring. In comparison to the dormancy-prone cells, metastatic cells display high class I PI3K activity. Counterintuitively, dormancy-prone cells display higher mTORC1 activity that could be attributed to a constant peripheral lysosomal positioning. Blocking this peripheral positioning reduced the DTC burden in the lungs and the incidence of visible metastases, suggesting that this might be a druggable survival mechanism for breast DTCs. In chapter three, we carried out an in vivo genome-wide knockout CRISPR screen in dormancy-prone cells, that put forward the uncharacterized gene, Mob3c, as a potential pro-dormancy gene. Mob3c expression level in models of dormancy in comparison with proliferative counterparts, supported the screen prediction of Mob3c potentially being a metastasis suppressor. Proteomics-based screens and protein-protein interaction assays suggested that MOB3C interacts with the endonuclease RNase P complex, that catalyzes different essential cellular functions including tRNA maturation. Metastatic relapse-focused clinical analyses (i.e., distant metastasis- and progression-free survival) in breast cancer patients validated the outlined preclinical findings in the two chapters, supporting a potential significance and impact of the revealed molecular insights.

Le cancer colorectal est la deuxième cause de mortalité due au cancer en Europe et aux États-Unis. Etant donné l’efficacité limitée et la toxicité élevée des agents de chimiothérapie, de nouvelles approches sont nécessaires. Le flavanolignane silybine représente le principal constituant actif du chardon-marie (Silybum marianum). Les mécanismes moléculaires des propriétés anticancéreuses de la silybine ont été étudiés dans un modèle cellulaire de progression du cancer colorectal humain : les cellules SW480 issues d’un adénocarcinome, et leurs dérivées métastatiques les cellules SW620. Les effets chimiopréventifs de la silybine ont été étudiés dans un modèle de cancérogenèse colique induite par l’azoxyméthane chez le rat. La silybine induit une mort apoptotique avec activation de la caspase-3 dans les deux lignées. L’expression des récepteurs de mort TRAIL est augmentée, et la caspase-8 activée. Le potentiel mitochondrial est perturbé provoquant une libération du cytochrome c et une activation de la caspase-9. En plus de l’activation des voies apoptotiques extrinsèque et intrinsèque la silybine induit une réponse autophagique. La combinaison de la silybine et de TRAIL, un agent anti-cancéreux prometteur, provoque une mort cellulaire synergique dans les deux lignées. Un effet synergique est aussi observé avec la combinaison de la silybine et des inhibiteurs des histones déacétylases (HDAC) : TSA et SAHA. Dans le modèle chez le rat, la silybine réduit de 50% le nombre des lésions prénéoplasiques. En conclusion, la silybine est un agent naturel intéressant pour la prévention du cancer colorectal et dans le cadre d’une combinaison avec TRAIL/des inhibiteurs d’HDACs. / Colorectal cancer (CRC) is the second most common cause for cancer-related deaths in Europe and in the USA. Because of the limited efficacy and considerable toxicity of chemotherapeutic agents, new approaches are needed. The hepatoprotective flavonolignan silibinin is the major biologically active compound of the milk thistle (Silybum marianum).The molecular mechanisms of the anticancer properties of silibinin in CRC were studied in an in vitro model of cancer progression consisting of the adenocarcinoma cell line SW480 and its derived metastatic cell line SW620. Its chemopreventive effects were assessed in an in vivo model of azoxymethane-induced colon carcinogenesis in the rat. Silibinin induced apoptotic cell death with activation of caspase-3 in both cell lines. The expression of death receptors was upregulated, and caspase-8 was activated. The potential of the mitochondrial membrane was perturbed permitting the release of cytochrome c and the activation of caspase-9. Besides the activation of the extrinsic and the intrinsic apoptotic pathway, silibinin induced an autophagic response. Combination of silibinin and TRAIL, a promising anticancer agent selectively inducing apoptosis in cancer cells, induced synergistic cell death in both cell lines. Synergy in cell death induction was also observed by the combination of silibinin and the histone deacetylase (HDAC) inhibitors TSA and SAHA. In the preclinical model in the rat, silibinin administration was able to reduce by half the number of preneoplastic lesions present in the colon. In conclusion, silibinin is a promising natural agent for colon cancer chemoprevention and for combination therapy with TRAIL/HDAC inhibitors.

Background: In the management of metastatic colorectal cancer (mCRC), KRAS, NRAS and BRAF mutational status individualizes therapeutic options and identify a cohort of patients (pts) with an aggressive clinical course. We hypothesized that relapsed and refractory mCRC pts develop unique mutational signatures that may guide therapy, predict for a response and highlight key signaling pathways important for clinical decision making. Methods: Relapsed and refractory mCRC pts (N=32) were molecularly profiled utilizing commercially available next generation sequencing (NGS) platforms. Web-based bioinformatics tools (Reactome/Enrichr) were utilized to elucidate mutational profile linked pathways-networks that have the potential to guide therapy. Results: Pts had progressed on fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, cetuximab and/or panitumumab. Most common histology was adenocarcinoma (colon N=29; rectal N=3). Of the mutations TP53 was the most common, followed by APC, KRAS, PIK3CA, BRAF, SMAD4, SPTA1, FAT1, PDGFRA, ATM, ROS1, ALK, CDKN2A, FBXW7, TGFBR2, NOTCH1 and HER3. Pts had on average had >= 5 unique mutations. The most frequent activated signaling pathways were: HER2, fibroblast growth factor receptor (FGFR), p38 through BRAF-MEK cascade via RIT and RIN, ARMS-mediated activation of MAPK cascade, and VEGFR2. Conclusions: Dominant driver oncogene mutations do not always equate to oncogenic dependence, hence understanding pathogenic ` interactome(s)' in individual pts is key to both clinically relevant targets and in choosing the next best therapy. Mutational signatures derived from corresponding ` pathway-networks' represent a meaningful tool to (I) evaluate functional investigation in the laboratory; (II) predict response to drug therapy; and (III) guide rational drug combinations in relapsed and refractory mCRC pts.

Metastatic epidural spinal cord compression (MESCC) occurs when tumour invades the epidural space and compresses the spinal cord. Despite Level 1 evidence that surgery is the most effective treatment for MESCC, there is controversy regarding the role of surgery because of fear that patients who have a short survival will spend a large fraction of their remaining life recovering from surgery and potential complications. This controversy could be resolved by decision-analysis of MESCC treatments using quality-adjusted-life-years (QALYs). There have been two barriers to conducting decision-analysis of QALYs for MESCC: (a) lack of utility data, and (b) skepticism regarding decision-analysis. The first four research chapters in this thesis address these barriers. The final research chapter reports a decision-analysis of QALYs on the role of surgery in MESCC. Chapter 1 provides background information on the controversy regarding surgical treatment for MESCC and the rationale for each of the subsequent chapters. Chapter 2 reports a psychometric validation study of a web-based utility valuation module for MESCC. In Chapter 3, application of this module to a general population utility valuation study with a market research panel is described. In Chapter 4, the beneficial properties of Bayesian statistical analysis to minimizing “arbitrariness” in probabilistic sensitivity analysis are described in relation to prognostication for MESCC. Chapter 5 presents a strategy for simplifying and enhancing the transparency of Markov cohort simulation. Finally, the work presented in the research chapters is applied in Chapter 6 to conduct Markov cohort simulation to determine if patients with short survival derive net health-related quality-of-life benefit from surgery. Pragmatic research around barriers to decision-analysis of QALYs for MESCC was conducted to resolve the controversy regarding the role of surgery in the treatment of MESCC. Under most circumstances, MESCC patients who can ambulate prior to treatment derive net HRQoL benefit from surgery, even if prognosis is poor. Non-ambulatory patients can derive net HRQoL benefit but only if the morbidity of surgery is relatively low. It is my hope that the work used to address barriers to decision-analysis of QALYs will be disseminated and applied in other clinical problems.

O melanoma metastático apresenta um alto grau de heterogeneidade, o que aumenta a dificuldade de sucesso no tratamento, com altos níveis de resistência e recidiva nos pacientes. Mesmo os avanços atuais não apresentaram a taxa de eficácia esperada no tratamento do melanoma. Estudos mostraram compostos de telúrio apresentando efeitos de seletividade em direção a células tumorais, poupando células saudáveis, chamado de efeito sensor efetor. Assim, testamos dois compostos orgânicos enantioméricos de telúrio sobre a biologia celular de linhagens de melanócitos e melanoma metastático. Os resultados mostraram que os compostos apresentam o efeito sensor efetor, e atuam sobre a morfologia das células tumorais sem afetar as células normais. Verificamos alterações de ciclo celular, entretanto não encontramos morte celular por ativação de caspase 9. Também encontramos efeitos genotóxicos para uma das linhagens. Os resultados encontrados colocam essas organoteluranas como promissoras drogas no tratamento de melanoma metastático. / Metastatic melanoma displays a high degree of heterogeneity, which increases difficulty of treatment success, with high levels of resistance and relapse in patients. Even the current advances have not shown the efficacy rate expected for the treatment of melanoma. Studies showed that tellurium compounds display selective effects towards tumour cells, sparing healthy ones, called sensor effector effect. Thus, we tested two enantiomeric organotellurium compounds on the cell biology of melanocyte and metastatic melanoma cell lines. Results showed that the compounds possess the sensor effector effect and act on tumour cells morphology without affecting healty cells. We found cell cycle alterations, however we did not find cell death by activation of caspse 9. We also found genotoxic effects for one of the cell lines. The results set these organotelluranes as promising drugs for the treatment of metastatic melanoma.

Bakgrund: Bröstcancer är den vanligaste cancerdiagnos som kvinnor världen över drabbas av. Metastaserad bröstcancer (MBC) innebär att bröstcancern har bildat dottertumörer. Världshälsoorganisationen (WHO) definierar livskvalitet som individens uppfattning av sin livssituation i relation till rådande kultur och normer, och i förhållande till sina egna mål, förväntningar, värderingar och intressen. För att mäta livskvaliteten används mätinstrument i forma av enkäter och skalor som innehåller frågor som är indelade i olika områden som påverkar livskvaliteten. Enligt Erikssons omvårdnadsteori är hälso- och sjukvårdens huvudsakliga uppgift att lindra lidandet hos den lidande människan som lever med en sjukdom. Syfte: Syftet är att belysa vilka faktorer som påverkar livskvaliteten hos kvinnor skriv med metastaserad bröstcancer. Metod: En litteraturöversikt som baseras på 15 vetenskapliga artiklar.  Resultat: Kvinnor som har metastaserad bröstcancer har en lägre livskvalitet jämfört med kvinnor som har en annan form av bröstcancer. Faktorer som påverkar livskvaliteten kan beskrivas utifrån fyra kategorier; livskvalitet relaterat till typ av metastasdiagnos, livskvalitet relaterat till sjukdomstid, livskvalitet relaterat till behandling och livskvalitet relaterat till kvinnans rollfunktion med underkategorin livskvalitet relaterat till kvinnans ålder.  Konklusion: Resultatet visar en majoritet av kvinnorna upplever en lägre livskvalitet efter besked om sin MBC-diagnos. Den minskade livskvaliteten resulterar i ett livslidande och sjukdomslidande hos kvinnorna. Det är av stor av vikt att sjuksköterskan ser till den lidande kvinnan och beaktar hennes behov och upplevelser. Sjuksköterskan bör även arbeta familjecentrerat för att kunna ge den bästa vården för kvinnan och hennes familj. / Background: Breast cancer is the most common cancer diagnosis that women worldwide experience. Metastatic breast cancer (MBC) means that the breast cancer has formed daughter tumors. The World Health Organization (WHO) defines quality of life as the individual's perception of his or her life situation in relation to current culture and norms, and in relation to his or her own goals, expectations, values and interests. To measure the quality of life, measuring instruments in the form of questionnaires and scales, used that contain questions that are divided into different areas that affect the quality of life. According to Eriksson's nursing theory, the main task of health care is to alleviate the suffering of the suffering person who lives with a disease. Aim: The aim is to highlight which factors affect the quality of life of women with metastatic breast cancer. Method: A literature review based on 15 scientific articles. Result: Women who have metastatic breast cancer have a lower quality of life compared to women who have a different form of breast cancer. Factors that affect the quality of life can be described by four categories that are; quality of life related to type of metastasis diagnosis, quality of life related to disease time, quality of life related to treatment and quality of life related to the woman's role function with the subcategory quality of life related to the woman's age. Conclusion: Most of the women in the thesis work experience a lower quality of life after being informed of their MBC diagnosis. The diminished quality of life results in a life-long and disease-suffering of women. It is of great importance that the nurse looks to the suffering woman and considers her needs and experiences. The nurse should also work family-centered in order to provide the best care for the woman and her family.

Polysialic acid (polySia) is a carbohydrate polymer highly expressed during embryonic development but rarely expressed during postnatal development. Two polysialyltransferase (polyST) enzymes are responsible for the synthesis of polySia: ST8SiaII and ST8SiaIV. During oncogenesis polySia is re-expressed and it modulates cell-cell and cell-matrix adhesion, migration, invasion and metastasis. PolySia expression is strongly associated with poor clinical prognosis and correlates with aggressive and invasive disease in neuroblastoma and many other tumours. PolyST inhibition thus presents a novel, selective and largely unexplored therapeutic opportunity to reduce tumour dissemination. Progress towards development of polyST inhibitors has been limited by lack of an efficient technique for quantitative assessment of enzyme activity. We have validated a highly sensitive cell-based and cell-free high throughput HPLC-based inhibition assays. Using isogenic cell lines (C6-STX: polySia+/ST8SiaII+ and C6-WT: polySia-/ST8SiaII-) and naturally polySia expressing human neuroblastoma cells (SH-SY5Y), a set of ST8SiaII inhibitors designed and synthesised in house were evaluated for their ability to reduce polySia expression and to modulate cell migration in vitro. We have identified CMP-sialic acid precursors, including ICT-3176, which reduced polySia expression and tumour cell migration by up to 70%. These effects were only found in cell lines expressing ST8SiaII and polySia. Furthermore, we have investigated the possible additive anti-migratory effect of combining polyST inhibition with the inhibition of certain signalling pathways that have been previously suggested to be modulated by polySia expression. Out of these combinations it was found that combining ST8SiaII and C-MET/ALK inhibition had a synergistic effect on inhibiting cancer cell migration. Additionally, the effect of polySia expression on cancer cell behaviour under hypoxic conditions was examined, where it was found that polySia expression enhanced cell migration and survival and inhibits cell adhesion. In summary, polyST inhibitors which dramatically decrease cell migration in vitro through modulation of polySia assembly were identified, using optimised cell-free and cell-based assays. Initial investigations into the role of polySia in hypoxia were also accomplished. This work paves the way for development of a novel therapeutic for the treatment of neuroblastoma.

Introdução: O câncer de próstata metastático resistente à castração apresenta sobrevida inferior a 30% em cinco anos, e o único tratamento disponível para os pacientes até pouco tempo atrás era o docetaxel. Com o maior entendimento dos mecanismos de resistência desse câncer às terapias utilizadas, novas drogas foram desenvolvidas, entre elas a abiraterona, que atua no bloqueio da enzima 17-? desidrogenase-hidroxiesteroide e a enzalutamida que age diretamente nos receptores de androgênios. Foi realizada uma revisão sistemática dos estudos que avaliaram a eficácia e segurança da abiraterona mais prednisona e da enzalutamida em pacientes com CPMRC, tanto previamente quanto posteriormente ao tratamento com docetaxel. Métodos: A pesquisa bibliográfica foi realizada em março de 2016 nas bases da Pubmed, Google Acadêmico e ClinicalTrials.gov. Os seguintes termos de pesquisa foram utilizados \"prostate cancer metastatic resistent\", \"prostate cancer\", \"abiraterone\" e enzalutamide\", restringido a estudos clínicos randomizados fase III, duplo cego e multicêntrico, publicados nos idiomas inglês, espanhol. Os estudos selecionados foram analisados de forma independente por LRM e AAN. Os critérios para análise foram a sobrevida global (SG), sobrevida livre de progressão (SLP) e o tempo até a progressão do PSA (TP PSA), previamente e após o uso de docetaxel. Resultados: Foram identificados 53 estudos. Aplicando os critérios de inclusão foram selecionados quatro estudos que juntos somaram uma população de 5.199 (2.394 pacientes após docetaxel e 2.805 pacientes previamente ao uso do docetaxel). Em relação a SG, a abiraterona reduziu o risco de morte em 26% após docetaxel (HR 0,74 95% IC 0,64-0,86) e 19% no pré-docetaxel (HR 0,81 95% IC 0,70-0,93), e a enzalutamida reduziu em 37% após (HR 0,63 95% IC, 0,53-0,75) e 23% no pré-docetaxel (HR 0,77 95% IC 0,67-0,88). Em relação a SLPr, abiraterona retardou a progressão da doença em 34% após (HR 0,66 95% IC 0,58-0,76) e 48% na pré-quimio (HR 0,52 95% IC 0,45-0,61), e a enzalutamida em 60% após quimio (HR 0,40 95% IC 0,35-0,47) e 68% na pré-quimio (HR 0,32 95% IC 0,28-0,36). Abiraterona aumentou o tempo até a progressão do PSA em 64% após quimio (HR 0,36 95% IC 0,52-0,78) e 50% na pré-quimio (HR 0,50 95% IC 0,43- 0,58), e a enzalutamida em 75% após quimio (HR 0,25 95% IC 0,20-0,30) e 83% na pré- quimio (HR 0,17 95% IC 0,15-0,20). Conclusão: Tanto abiraterona quanto enzalutamida demonstraram melhores resultados no aumento da SG, da SLPr e do TP PSA no tratamento de pacientes com CPMRC. Não há um estudo comparativo direto e devido a diferenças nos critérios de inclusão e dos grupos comparadores entre esses estudos clínicos, não é possível uma análise indireta entre tais medicamentos. Assim, questões como qual a melhor estratégia de tratamento na pré e pós-quimio e o sequenciamento ideal para enfrentamento do CPMRC não podem ser respondidas. / Introduction: Castrate-resistant metastatic prostate cancer presents survival less than 30% in five years, and the only treatment available to patients until recently was docetaxel. With the greater understanding of the mechanisms of resistance of this cancer to the therapies used, new drugs have been developed, among them abiraterone, which acts in the blockade of the enzyme 17-? dehydrogenase-hydroxysteroid and the enzyme that acts directly on the androgen receptors. A systematic review was made of studies evaluating the efficacy and safety of abiraterone plus prednisone and of enzyme adduct in patients with CPMRC both before and after docetaxel treatment. Methods: The literature search was prepared in March 2016 based on Pubmed, Google Scholar and ClinicalTrials.gov. The following search terms were used \"prostate cancer metastatic resistant\", \"prostate cancer\", \"abiraterone\" and \"enzyme\", restricted to phase III, double blind and multicenter clinical trials published in English, Spanish, Italian and Portuguese. The selected studies were analyze by LRM and AAN. The criteria for analysis were overall survival (OS), progression-free survival (PSA) and time to PSA progression (PS PSA), before and after docetaxel use. Results: Fifty-three studies were identified and, according to the inclusion criteria, four studies were selected that together added a population of 5,199 (2,394 patients after docetaxel and 2,805 patients prior to docetaxel use). In relation to SG, abiraterone reduced the risk of death by 26% after docetaxel (HR 0.74 95% CI 0.64-0.86) and 19% in predocetaxel (HR 0.81 95% CI 0.70- 0.93), and enzyme reductase reduced by 37% (HR 0.63 95% CI, 0.53-0.75) and 23% in pre docetaxel (HR 0.77 95% CI 0.67-0, 88). In relation to SLPr abiraterone delayed disease progression by 34% (HR 0.66 95% CI 0.58-0.76) and 48% in pre-chemotherapy (HR 0.52 95% CI 0.45-0, 61), and enzyme-alpha 60% after chemo (HR 0.40 95% CI 0.35-0.47) and 68% in pre-chemo (HR 0.32 95% CI 0.28-0.36). Abiraterone increased the time until PSA progression by 64% after chemo (HR 0.36 95% CI 0.52-0.78) and 50% in pre-chemo (HR 0.50 95% CI 0.43-0, 58), and enzyme-alpha in 75% after chemo (HR 0.25 95% CI 0.20-0.30) and 83% in pre-chemo (HR 0.17 95% CI 0.15-0.20). Conclusion: Both abiraterone and enzalutamide showed better results in increasing SG, SLPr and TP PSA in the treatment of patients with CPMRC. There is no direct comparative study and, because of differences in inclusion criteria and comparator groups between these clinical studies, indirect analysis of such drugs is not possible. Thus, questions such as the best pre and post chemo treatment strategy and the optimal sequencing for CPMRC coping cannot be answered.

Multiple research studies have demonstrated racial, socioeconomic status (SES), and neighborhood disparities in first-line treatment of colorectal cancer patients, including those with metastatic colorectal cancer. However, disparities in adjunct monoclonal antibody treatment disparities have not been explored. The purpose of this study was to assess racial, SES, and neighborhood disparities in adjunct monoclonal antibody treatment of elderly metastatic colorectal cancer patients. The research was rooted in 3 theories: the fundamental cause theory, the diffusion of innovations theory, and theory of health disparities and medical technology. Data from the SEER-Medicare database and logistic regression were used to assess the relationship between the variables of interest and adjunct monoclonal antibody therapy. In this study, race (p = 0.070), SES (p = 0.881), and neighborhood characteristics (p = 0.309) did not significantly predict who would receive monoclonal antibody therapy. The results demonstrated a potential improvement in historically documented colorectal cancer treatment disparities. Specifically, historical treatment disparities may not be relevant to newer therapies prescribed to patients with severe disease. The difference could be related to improved access to care or a change in treatment paradigm due to the severity of metastatic colorectal cancer. Future studies aimed at understanding the causes of this social change (i.e., reduced treatment disparities) are warranted. Understanding the root cause of the reduced treatment disparities observed in this study could be used to reduce treatment disparities in other cancer populations.

Background: Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality. About 50 % of patients with CRC will develop subsequent liver metastases (CLM). The survival for untreated CLM is only a few months and liver resection provides the only chance for a lasting cure. It is therefore essential to detect CLM early, enabling successful surgical resection and achieving a long-term cure. There are no optimal tumour markers for CRC or CLM. The best marker available is Carcinoembryonic Antigen (CEA), a marker found elevated in about 50-60% of patients with CLM, but also in many other conditions. The main focus of cancer research has been on the malignant cancer cell. However, a tumour consists of more than cancer cells. A major part of all solid tumours is made up by the stroma. The tumour stroma is defined as the non-malignant cells of a tumour such as fibroblasts, the cells of the vascular and immune systems as well as the extracellular matrix (ECM). The basement membrane (BM) is a specialized form of the ECM in which type IV collagen is the major protein component. All epithelial cells need a contact to the BM and the definition of an invasive cancer is the degradation of the BM and the spread of cancer cells beyond this structure. Different metastatic growth patterns of CLM have previously been described, namely the desmoplastic, pushing and replacement type of CLM. These differ in their stromal reaction in the border, which separates the tumour from the normal liver. In this thesis the tumour stroma of CRC and CLM is studied with a special emphasis on stromal collagens. The aim is to investigate whether stromal collagens/ circulating type IV collagen can be used as tumour markers for CRC and CLM, and to compare this to the conventional marker CEA. The circulating type IV collagen level is also measured in liver metastases from other primary tumours than CRC. Furthermore, the differences between the stroma of a primary CRC that metastasizes to the liver when compared to a CRC that never spreads are analysed. Additionally, the metastatic growth pattern of CLM is studied in relation to the primary tumour, stromal components and survival. We also sought out to find whether CRC cell lines possess the trait to produce ECM proteins endogenously, and in response to a normal liver stroma in a novel organotypic model for CLM. Methods: Expression patterns of type I, III and IV collagen were studied by immunofluorescence (IF), chemical staining and immunohistochemistry (IHC) in normal colorectal tissue, normal liver, CRC, CLM, benign liver lesions and in liver metastases of other origin than CRC. Circulating plasma levels of type IV collagen were analysed in healthy controls, patients with CRC (T stage I-III) and in patients with CLM. Samples were analysed at the time of diagnosis, during and after oncological and surgical treatment and at the time of relapsing or progressive disease. Additionally, circulating levels were analysed in patients with benign liver lesions and in liver metastases of other origin than CRC. The metastatic growth pattern of CLM was classified according to earlier descriptions. CRC cell lines were studied regarding their production of type IV collagen. The growth, invasiveness and stromal production in CRC cell lines were also investigated in a new organotypic model for CLM using human liver specimens. Results: Circulating type IV collagen levels are increased in patients with CLM and other epithelial-derived liver metastases, and is found normal in patients with primary CRC (stage I-III), with liver metastases from tumours of non-epithelial origin, benign liver lesions and in healthy controls. The type IV collagen levels in patients with CLM reflect the tumour burden in the liver, decreases in response to therapy and is found increased in progressive or relapsing disease. The combination of circulating type IV collagen and CEA increased the sensitivity and specificity for detecting CLM. Livermetastatic CRC displayed an increased stromal production when compared to non-metastatic CRC, with an increased type IV collagen expression in the direct vicinity of the CRC cells. The earlier described growth patterns of CLM were verified, with the pushing type of CLM associated with a short survival and poor outcome. Furthermore, CRC cell lines possess the trait of endogenously producing type IV collagen. The novel organotypic liver model revealed that CRC cell lines grown in the context of normal liver stroma, devoid of other cells, does not elicit a desmoplastic reaction. Conclusion: Circulating type IV collagen is a promising tumour marker for CLM, where the levels reflect the hepatic tumour burden and can detect disease relapse after liver surgery. The combination of the tumour markers CEA and type IV collagen is superior to CEA alone. The stromal composition of primary CRC predicts the risk of subsequent CLM and the metastatic growth pattern of CLM is related to survival.