[Show abstract][Hide abstract] ABSTRACT: Hierarchical organized tissue structures, with stem cell driven cell differentiation, are critical to the homeostatic maintenance of most tissues, and this underlying cellular architecture is potentially a critical player in the development of a many cancers. Here, we develop a mathematical model of mutation acquisition to investigate how deregulation of the mechanisms preserving stem cell homeostasis contributes to tumor initiation. A novel feature of the model is the inclusion of both extrinsic and intrinsic chemical signaling and interaction with the niche to control stem cell self-renewal. We use the model to simulate the effects of a variety of types and sequences of mutations and then compare and contrast all mutation pathways in order to determine which ones generate cancer cells fastest. The model predicts that the sequence in which mutations occur significantly affects the pace of tumorigenesis. In addition, tumor composition varies for different mutation pathways, so that some sequences generate tumors that are dominated by cancerous cells with all possible mutations, while others are primarily comprised of cells that more closely resemble normal cells with only one or two mutations. We are also able to show that, under certain circumstances, healthy stem cells diminish due to the displacement by mutated cells that have a competitive advantage in the niche. Finally, in the event that all homeostatic regulation is lost, exponential growth of the cancer population occurs in addition to the depletion of normal cells. This model helps to advance our understanding of how mutation acquisition affects mechanisms that influence cell-fate decisions and leads to the initiation of cancers.
[Show abstract][Hide abstract] ABSTRACT: Many fraudulent nucleosides including the antivirals acyclovir (ACV) and ganciclovir (GCV) must be metabolized to triphosphates to be active. Cyclopropavir (CPV) is a newer, related guanosine nucleoside analog that is active against human cytomegalovirus (HCMV) in vitro and in vivo. We have previously demonstrated that CPV is phosphorylated to its monophosphate (CPV-MP) by the HCMV pUL97 kinase. Consequently, like other nucleoside analogs phosphorylated by viral kinases, CPV most likely must be converted to a triphosphate (CPV-TP) in order to elicit antiviral activity. Once formed by pUL97, we hypothesized that guanosine monophosphate kinase (GMPK) is the enzyme responsible for the conversion of CPV-MP to CPV-DP. Incubation of CPV-MP with GMPK resulted in the formation of CPV-DP and, surprisingly, CPV-TP. When CPV-DP was incubated with GMPK, a time-dependent increase in CPV-TP occurred corresponding to a decrease in CPV-DP thereby demonstrating that CPV-DP is a substrate for GMPK. Substrate specificity experiments revealed that GMP, dGMP, GDP, and dGDP are substrates for GMPK. In contrast, GMPK recognized only acyclovir and ganciclovir monophosphates as substrates, not their diphosphates. Kinetic studies demonstrated that CPV-DP has a K(M) value of 45±15μM. We were, however, unable to determine the K(M) value for CPV-MP directly, but a mathematical model of experimental data gave a theoretical K(M) value for CPV-MP of 332±60μM. We conclude that unlike many other antivirals, cyclopropavir can be converted to its active triphosphate by a single cellular enzyme once the monophosphate is formed by a virally encoded kinase.
Full-text · Article · Jan 2011 · Biochemical pharmacology
[Show abstract][Hide abstract] ABSTRACT: Most mammalian tissues are organized into a hierarchical structure of stem,
progenitor, and differentiated cells. Tumors exhibit similar hierarchy, even if
it is abnormal in comparison with healthy tissue. In particular, it is believed
that a small population of cancer stem cells drives tumorigenesis in certain
malignancies. These cancer stem cells are derived from transformed stem cells or
mutated progenitors that have acquired stem-cell qualities, specifically the
ability to self-renew. Similar to their normal counterparts, cancer stem cells
are long-lived, can self-renew and differentiate, albeit aberrantly, and are
capable of generating tissue, resulting in tumor formation. Although identified
and characterized in several forms of malignancy, the specific multi-step
process that causes the formation of cancer stem cells is uncertain. Here, a
maturity-structured mathematical model is developed to investigate the
sequential order of mutations that causes the fastest emergence of cancer stem
cells. Using model predictions, we discuss conditions for which genetic
instability significantly speeds cancer onset and suggest that unbalanced
stem-cell self-renewal and inhibition of progenitor differentiation contribute
to aggressive forms of cancer. To our knowledge, this is the first continuous
maturity-structured mathematical model used to investigate mutation acquisition
within hierarchical tissue in order to address implications of cancer stem cells
Preview · Article · Dec 2008 · Mathematical Modelling of Natural Phenomena
[Show abstract][Hide abstract] ABSTRACT: Most adult tissues consist of stem cells, progenitors, and mature cells, and this hierarchical architecture may play an important role in the multistep process of carcinogenesis. Here, we develop and discuss the important predictions of a simple mathematical model of cancer initiation and early progression within a hierarchically structured tissue. This work presents a model that incorporates both the sequential acquisition of phenotype altering mutations and tissue hierarchy. The model simulates the progressive effect of accumulating mutations that lead to an increase in fitness or the induction of genetic instability. A novel aspect of the model is that symmetric self-renewal, asymmetric division, and differentiation are all incorporated, and this enables the quantitative study of the effect of mutations that deregulate the normal, homeostatic stem cell division pattern. The model is also capable of predicting changes in both tissue composition and in the progression of cells along their lineage at any given time and for various sequences of mutations. Simulations predict that the specific order in which mutations are acquired is crucial for determining the pace of cancer development. Interestingly, we find that the importance of genetic stability differs significantly depending on the physiological expression of mutations related to symmetric self-renewal and differentiation of stem and progenitor cells. In particular, mutations that lead to the alteration of the stem cell division pattern or the acquisition of some degree of immortality in committed progenitors lead to an early onset of cancer and diminish the impact of genetic instability.
Preview · Article · Dec 2008 · Neoplasia (New York, N.Y.)
[Show abstract][Hide abstract] ABSTRACT: Stem cells are proposed to segregate chromosomes asymmetrically during self-renewing divisions so that older ('immortal') DNA strands are retained in daughter stem cells whereas newly synthesized strands segregate to differentiating cells. Stem cells are also proposed to retain DNA labels, such as 5-bromo-2-deoxyuridine (BrdU), either because they segregate chromosomes asymmetrically or because they divide slowly. However, the purity of stem cells among BrdU-label-retaining cells has not been documented in any tissue, and the 'immortal strand hypothesis' has not been tested in a system with definitive stem cell markers. Here we tested these hypotheses in haematopoietic stem cells (HSCs), which can be highly purified using well characterized markers. We administered BrdU to newborn mice, mice treated with cyclophosphamide and granulocyte colony-stimulating factor, and normal adult mice for 4 to 10 days, followed by 70 days without BrdU. In each case, less than 6% of HSCs retained BrdU and less than 0.5% of all BrdU-retaining haematopoietic cells were HSCs, revealing that BrdU has poor specificity and poor sensitivity as an HSC marker. Sequential administration of 5-chloro-2-deoxyuridine and 5-iodo-2-deoxyuridine indicated that all HSCs segregate their chromosomes randomly. Division of individual HSCs in culture revealed no asymmetric segregation of the label. Thus, HSCs cannot be identified on the basis of BrdU-label retention and do not retain older DNA strands during division, indicating that these are not general properties of stem cells.
[Show abstract][Hide abstract] ABSTRACT: Most mammalian tissues are organized into a hierarchical structure of stem, progenitor, and differentiated cells. Tumors exhibit similar hierarchy, even if it is abnormal in comparison with healthy tissue. In particular, it is believed that a small population of cancer stem cells drives tumorigenesis. These cancer stem cells are derived from transformed stem cells or mutated progenitors that have acquired stem-cell qualities, specifically the ability to self-renew. Similar to their normal counterparts, cancer stem cells are long-lived, can self-renew and differentiate, albeit aberrantly, and are capable of generating tissue, resulting in tumor formation. Cancer stem cells have been identified and characterized in several forms of malignancy, but the specific multi-step process that causes their formation is uncertain. In this dissertation, a mathematical model is developed to investigate the role of cancer stem cells in tumorigenesis. With the application of a maturity-structured model, three primary aspects of cancer dynamics are discussed: (1) the sequential order of mutations that causes the fastest emergence of cancer stem cells, (2) the impact of deregulated mechanisms that normally govern homeostasis in hierarchical tissue, and (3) the evolving tissue composition as disease progresses with particular focus on the cancer stem cell population. Model predictions suggest that unbalanced stem-cell self-renewal and inhibition of progenitor differentiation contribute to aggressive forms of cancer. In addition, the continuous maturity structure is a novel feature of this model that is particularly effective in capturing the dynamics of immature blast accumulation in the progression of Chronic Myelogenous Leukemia. Simulating this specific form of cancer highlights potential modeling contributions to the scientific community, as the mathematical framework may be used to investigate additional forms of malignancy in hierarchical tissues. Ph.D. Applied and Interdisciplinary Mathematics University of Michigan, Horace H. Rackham School of Graduate Studies http://deepblue.lib.umich.edu/bitstream/2027.42/61753/1/sheusel_1.pdf