Cancer Stem Cell Hypothesis: Implication for Cancer Prevention and Treatment

BACKGROUND: Cancer is a disease of genomic instability, evasion of immune cells, and adaptation of the tumor cells to the changing environment. Genetic heterogeneity caused by tumors and tumor microenvironmental factors forms the basis of aggressive behavior of some cancer cell populations.CONTENT: Cancers arise in self-renewing cell populations and that the resulting cancers, like their normal organ counterparts, are composed of hierarchically organized cell populations. Self – renewing “cancer stem cells” (CSC) maintain tumor growth and generate the diverse populations constituting the tumor bulk. CSCs in multiple tumor types have been demonstrated to be relatively resistant to radiation and chemotherapy. The clinical relevance of these studies has been supported by neoadjuvant breast cancer trials that demonstrated increases in the proportions of CSCs after therapy. The CSC hypothesis has tremendously important clinical implications.SUMMARY: In summary, a large and accumulating body of evidence supports the CSC hypothesis, which has important implications for cancer prevention and therapy. The ultimate test of this hypothesis will require clinical trials demonstrating that targeting of these pathways reduces cancer incidence and improves outcomes for patients with cancer

Discovery of the cancer stem cell related determinants of radioresistance

AbstractTumors are known to be heterogeneous containing a dynamic mixture of phenotypically and functionally different tumor cells. The two concepts attempting to explain the origin of intratumor heterogeneity are the cancer stem cell hypothesis and the clonal evolution model. The stochastic model argues that tumors are biologically homogenous and all cancer cells within the tumor have equal ability to propagate the tumor growth depending on continuing mutations and selective pressure. By contrast, the stem cells model suggests that cancer heterogeneity is due to the hierarchy that originates from a small population of cancer stem cells (CSCs) which are biologically distinct from the bulk tumor and possesses self-renewal, tumorigenic and multilineage potential. Although these two hypotheses have been discussed for a long time as mutually exclusive explanations of tumor heterogeneity, they are easily reconciled serving as a driving force of cancer evolution and diversity. Recent discovery of the cancer cell plasticity and heterogeneity makes the CSC population a moving target that could be hard to track and eradicate. Understanding the signaling mechanisms regulating CSCs during the course of cancer treatment can be indispensable for the optimization of current treatment strategies

The role of acidity in tumour development

Acidic pH is a common characteristic of human tumours. It has a significant impact on tumour progression and response to therapies. In this thesis, we utilise mathematical modelling to examine the role of acidosis in the interaction between normal and tumour cell populations. In the first section we investigate the cell–microenvironmental interactions that mediate somatic evolution of cancer cells. The model predicts that selective forces in premalignant lesions act to favour cells whose metabolism is best suited to respond to local changes in oxygen, glucose and pH levels. In particular the emergent cellular phenotype, displaying increased acid production and resistance to acid-induced toxicity, has a significant proliferative advantage because it will consistently acidify the local environment in a way that is toxic to its competitors but harmless to itself. In the second section we analyse the role of acidity in tumour growth. Both vascular and avascular tumour dynamics are investigated, and a number of different behaviours are observed. Whilst an avascular tumour always proceeds to a benign steady state, a vascular tumour may display either benign or invasive dynamics, depending on the value of a critical parameter. Extensions of the model show that cellular quiescence, or non-proliferation, may provide an explanation for experimentally observed cycles of acidity within tumour tissue. Analysis of both models allows assessment of novel therapies directed towards changing the level of acidity within the tumour. Finally we undertake a comparison between experimental tumour pH images and the models of acid dynamics set out in previous chapters. This analysis will allow us to assess and verify the previous modelling work, giving the mathematics a firm biological foundation. Moreover, it provides a methodology of calculating important diagnostic parameters from pH images

SOX transcription factors and glioma stem cells: Choosing between stemness and differentiation

Glioblastoma (GBM) is the most common, most aggressive and deadliest brain tumor. Recently, remarkable progress has been made towards understanding the cellular and molecular biology of gliomas. GBM tumor initiation, progression and relapse as well as resistance to treatments are associated with glioma stem cells (GSCs). GSCs exhibit a high proliferation rate and self-renewal capacity and the ability to differentiate into diverse cell types, generating a range of distinct cell types within the tumor, leading to cellular heterogeneity. GBM tumors may contain different subsets of GSCs, and some of them may adopt a quiescent state that protects them against chemotherapy and radiotherapy. GSCs enriched in recurrent gliomas acquire more aggressive and therapy-resistant properties, making them more malignant, able to rapidly spread. The impact of SOX transcription factors (TFs) on brain tumors has been extensively studied in the last decade. Almost all SOX genes are expressed in GBM, and their expression levels are associated with patient prognosis and survival. Numerous SOX TFs are involved in the maintenance of the stemness of GSCs or play a role in the initiation of GSC differentiation. The fine-tuning of SOX gene expression levels controls the balance between cell stemness and differentiation. Therefore, innovative therapies targeting SOX TFs are emerging as promising tools for combatting GBM. Combatting GBM has been a demanding and challenging goal for decades. The current therapeutic strategies have not yet provided a cure for GBM and have only resulted in a slight improvement in patient survival. Novel approaches will require the fine adjustment of multimodal therapeutic strategies that simultaneously target numerous hallmarks of cancer cells to win the battle against GBM

From cancer cell plasticity to differentiation therapy

Cancer is a systemic heterogeneous disease that can undergo several rounds of latency and activation. Malignant tumours evolve by increasing diversity and in progressive response to microenvironment signals and resistance development after therapeutic interventions. Thus, adaptation is required for cancer cell survival during tumour dissemination and metastatic outgrowth. An epithelial-mesenchymal transition (EMT) plays a major role in facilitating cell plasticity in cancer and allows cancer cells to escape chemotherapy and targeted therapies by dedifferentiation and signalling adaption processes. EMT commonly describes a process in which differentiated epithelial cells lose their epithelial characteristics such as cellcell adhesions and apical-basal polarity and gain migratory properties. While an EMT is mainly responsible for primary tumour cell invasion, its reversal mesenchymal-epithelial plasticity (MET) has been shown to contribute to the metastatic outgrowth of disseminated cancer cells in distant organs. Hence, the therapeutic reversion of an EMT in cancer could be counterproductive. However, it has also been noted that cells undergoing an EMT and/or an MET are in a state of high cell plasticity and thus, may offer a window of opportunity for therapeutic targeting. Here, I have aimed at utilizing breast cancer cell plasticity by inducing terminal differentiation into postmitotic adipocytes. Giving the inherent growth arrest of adipocytes they are unlikely to adapt and dedifferentiate, and therefore lose cellular plasticity. I report the efficient conversion of breast cancer cells, which have undergone an EMT, into functional post-mitotic adipocytes. By combining the diabetic drug Rosiglitazone and bone morphogenetic protein 2 (BMP2) I have been able to achieve almost 100% adipogenesis efficiency in mesenchymal breast cancer cells in vitro. Delineation of the molecular pathways underlying such trans-differentiation has motivated a combination therapy with a MEK inhibitor and Rosiglitazone to demonstrate the conversion of invasive cancer cells into adipocytes and the repression of primary tumour invasion and metastasis formation in mouse models of breast cancer. The results indicate the high potential of utilizing the increased cell plasticity inherent to invasive cancer cells for differentiation therapy. They consequently raise the possibility of employing pharmacological treatments to interfere with tumour invasion and metastasis

Immune Regulatory Network in Cervical Cancer Development: The Expanding Role of Innate Immunity Mechanisms

There is increasing evidence of a pivotal regulatory role of innate immune mechanisms in tumor-immune interplay. Among these diverse mechanisms, tumor-derived nucleic acids’ sensing has recently emerged as one of the fundamental pathways linking innate and adaptive immunity, with DNA-sensor STING being the crucial member of this pathway. Another clear trend is understanding the striking diversity of innate and innate-like immune cell populations implicated in suppression or promotion of tumor growth. Papillomavirus-associated cervical cancer appears to represent a complex network of antiviral and antitumor innate immune mechanisms, whose regulation can be significantly influenced by developing neoplasia. In this chapter, we address new data on the problem of regulation of innate and acquired immunity in cervical cancer patients published in the past 2 years. To support the idea of multilevelness and diversity of changes in the innate arm of immunity, we also report our findings about (a) the expression of endogenous immune sensor STING in neoplastic tissue and peripheral blood lymphocytes, (b) altered frequencies of circulating natural killer and natural killer-like cell populations, as well as regulatory T lymphocytes from patients with precancerous or early cancerous lesions. Revisiting this problem may provide new insights into therapeutic options for cervical cancer