A Possible Explanation for the Variable Frequencies of Cancer Stem Cells in Tumors

A controversy surrounds the frequency of cancer stem cells (CSCs) in solid tumors. Initial studies indicated that these cells had a frequency ranging from to of the total cells. Recent studies have shown that this does not always seem to be the case. Some of these studies have indicated a frequency of . In this paper we propose a stochastic model that is able to capture this potential variability in the frequency of CSCs among the various type of tumors. Considerations regarding the heterogeneity of the tumor cells and its consequences are included. Possible effects on conventional treatments in clinical practice are also described. The model results suggest that traditional attempts to combat cancer cells with rapid cycling can be very stimulating for the cancer stem cell populations.     

Radiotherapy promotes tumor-specific effector CD8+ T cells via dendritic cell activation

Radiotherapy is an important treatment for cancer. The main mode of action is thought to be the irreversible damage to tumor cell DNA, but there is evidence that irradiation mobilizes tumor-specific immunity, and recent studies showed that the efficacy of high-dose radiotherapy depends on the presence of CD8(+) T cells. We show in this study that the efficacy of radiotherapy given as a single, high dose (10 Gy) crucially depends on dendritic cells and CD8(+) T cells, whereas CD4(+) T cells or macrophages are dispensable. We show that local high-dose irradiation results in activation of tumor-associated dendritic cells that in turn support tumor-specific effector CD8(+) T cells, thus identifying the mechanism that underlies radiotherapy-induced mobilization of tumor-specific immunity. We propose that in the absence of irradiation, the activation status of dendritic cells rather than the amount of tumor-derived Ag is the bottleneck, which precludes efficient anti-tumor immunity.     

A unified theory for the development of cancer

It is postulated that cancer is the result of genetic and epigenetic changes that occur mainly in stem (precursor) cells of various cell types. I propose that there are three classes of genes which are involved in the development of cancer. These are: Class I, II and III oncogenes. The classification is based on the way the oncogene acts at the cellular level to further the development of cancer. Genetic changes, that is point mutations, deletions, inversions, amplifications and chromosome translocations, gains or losses in the genes themselves or epigenetic changes in the genes (e.g. DNA hypomethylation) or in the gene products (RNA or protein) are responsible for the development of cancer. Changes of oncogene activity have a genetic or epigenetic origin or both and result in quantitative or qualitative differences in the oncogene products. These are involved in changing normal cells into the cells demonstrating a cancer phenotype (usually a form of dedifferentiated cell) in a multistep process. There are several pathways to cancer and the intermediate steps are not necessarily defined in an orderly fashion. Activation of a particular Class I or II oncogene and inactivation of a Class III oncogene could occur at any step during the development of cancer. Most benign or malignant tumors consist of a heterogeneous mixture of dedifferentiated cells arising from a single cell.     

Rethinking temperature sensitivity of the suprachiasmatic nucleus

A report by Buhr et al. (2010) proposed that the suprachiasmatic nucleus (SCN) is resistant to phase shifts induced by heat pulses and to entrainment by temperature cycles. These findings are inconsistent with those from studies by other laboratories in which the SCN readily phase shifts in response to heat pulses. I propose that their negative findings are not due to the SCN being temperature insensitive but are based on an explant culture preparation that does not fully express the properties of the SCN that are present in other in vitro preparations.     

Prostate cancer bone metastases promote both osteolytic and osteoblastic activity

Advanced prostate cancer is frequently accompanied by the development of metastasis to bone. In the past, prostate cancer bone metastases were characterized as being osteoblastic (i.e., increasing bone density) based on radiographs. However, emerging evidence suggests that development of prostate cancer bone metastases requires osteoclastic activity in addition to osteoblastic activity. The complexities of how prostate tumor cells influence bone remodeling are just beginning to be elucidated. Prostate cancer cells produce a variety of pro-osteoblastic factors that promote bone mineralization. For example, both bone morphogenetic proteins and endothelin-1 have well recognized pro-osteoblastic activities and are produced by prostate cancer cells. In addition to factors that enhance bone mineralization prostate cancer cells produced factors that promote osteoclast activity. Perhaps the most critical pro-osteoclastogenic factor produced by prostate cancer cells is receptor activator of NFkappaB ligand (RANKL), which has been shown to be required for the development of osteoclasts. Blocking RANKL results in inhibiting prostate cancer-induced osteoclastogenesis and inhibits development and progression of prostate tumor growth in bone. These findings suggest that targeting osteoclast activity may be of therapeutic benefit. However, it remains to be defined how prostate cancer cells synchronize the combination of osteoclastic and osteoblastic activity. We propose that as the bone microenvironment is changed by the developing cancer, this in turn influences the prostate cancer cells' balance between pro-osteoclastic and pro-osteoblastic activity. Accordingly, the determination of how the prostate cancer cells and bone microenvironment crosstalk are important to elucidate how prostate cancer cells modulate bone remodeling.     

Mobile phones, heat shock proteins and cancer

There are several reports which indicate that electromagnetic radiation (such as from mobile phones) at non-thermal levels may elicit a biological effect in target cells or tissues. Whether or not these biological effects lead to adverse health effects, including cancer, is unclear. To date there is limited scientific evidence of health issues, and no mechanism by which mobile phone radiation could influence cancer development. In this paper, we develop a theoretical mechanism by which radiofrequency radiation from mobile phones could induce cancer, via the chronic activation of the heat shock response. Upregulation of heat shock proteins (Hsps) is a normal defence response to a cellular stress. However, chronic expression of Hsps is known to induce or promote oncogenesis, metastasis and/or resistance to anticancer drugs. We propose that repeated exposure to mobile phone radiation acts as a repetitive stress leading to continuous expression of Hsps in exposed cells and tissues, which in turn affects their normal regulation, and cancer results. This hypothesis provides the possibility of a direct association between mobile phone use and cancer, and thus provides an important focus for future experimentation.     

From cancer metabolism to new biomarkers and drug targets

Great interest is presently given to the analysis of metabolic changes that take place specifically in cancer cells. In this review we summarize the alterations in glycolysis, glutamine utilization, fatty acid synthesis and mitochondrial function that have been reported to occur in cancer cells and in human tumors. We then propose considering cancer as a system-level disease and argue how two hallmarks of cancer, enhanced cell proliferation and evasion from apoptosis, may be evaluated as system-level properties, and how this perspective is going to modify drug discovery. Given the relevance of the analysis of metabolism both for studies on the molecular basis of cancer cell phenotype and for clinical applications, the more relevant technologies for this purpose, from metabolome and metabolic flux analysis in cells by Nuclear Magnetic Resonance and Mass Spectrometry technologies to positron emission tomography on patients, are analyzed. The perspectives offered by specific changes in metabolism for a new drug discovery strategy for cancer are discussed and a survey of the industrial activity already going on in the field is reported.     

Quiescence: early evolutionary origins and universality do not imply uniformity

Cell cycle investigations have focused on relentless exponential proliferation of cells, an unsustainable situation in nature. Proliferation of cells, whether microbial or metazoan, is interrupted by periods of quiescence. The vast majority of cells in an adult metazoan lie quiescent. As disruptions in this quiescence are at the foundation of cancer, it will be important for the field to turn its attention to the mechanisms regulating quiescence. While often presented as a single topic, there are multiple forms of quiescence each with complex inputs, some of which are tied to conceptually challenging aspects of metazoan regulation such as size control. In an effort to expose the enormity of the challenge, I describe the differing biological purposes of quiescence, and the coupling of quiescence in metazoans to growth and to the structuring of tissues during development. I emphasize studies in the organism rather than in tissue culture, because these expose the diversity of regulation. While quiescence is likely to be a primitive biological process, it appears that in adapting quiescence to its many distinct biological settings, evolution has diversified it. Consideration of quiescence in different models gives us an overview of this diversity.     

Do TNF-alpha-insensitive cancer cells escape alpha-tubulin nitrotyrosination?

TNF-alpha induces tumor-selective cytotoxicity in certain cancers, but many tumors are resistant to the effects of this inflammatory cytokine. This brief hypothesis outlines my views that nitric oxide-mediated alpha-tubulin posttranslational nitrotyrosination may be a major mechanism through which TNF-alpha exerts its cytotoxic effects on cancer cells. Additionally, I propose that tumor cells that are resistant to the effects of TNF-alpha may be so because of suppressed levels of "tubulin tyrosine ligase," which is responsible for the posttranslational tyrosination of alpha-tubulin.     

Telomeres and lifestyle factors: roles in cellular aging

Recent research has demonstrated that telomere maintenance might be a key integrating point for the cumulative effects of genetic, environmental and lifestyle factors on aging and aging-related diseases. It is timely to 'take stock' of where this work has led the field. This review summarizes studies that have examined associations between lifestyle factors and telomere length and telomerase activity. In most of the studies described in this chapter, telomere length was measured in leukocytes (LTL) or peripheral blood mononuclear cells (PBMCs), taken from blood draws from the study subjects. Much of this chapter focuses on psychological stress, a widespread factor often intimately tied in with lifestyle or behavioral factors that in turn are related to risks of clinical diseases. Together, these findings suggest that cellular aging is linked to a range of influences, with an individual's life events and lifestyle parameters playing significant roles. Lastly, we propose possible biochemical mechanisms that mediate these associations and discuss future directions.     

Tumorigenesis as a process of gradual loss of original cell identity and gain of properties of neural precursor/progenitor cells

Cancer is a complex disease without a unified explanation for its cause so far. Our recent work demonstrates that cancer cells share similar regulatory networks and characteristics with embryonic neural cells. Based on the study, I will address the relationship between tumor and neural cells in more details. I collected the evidence from various aspects of cancer development in many other studies, and integrated the information from studies on cancer cell properties, cell fate specification during embryonic development and evolution. Synthesis of the information strongly supports that cancer cells share much more similarities with neural progenitor/stem cells than with mesenchymal-type cells and that tumorigenesis represents a process of gradual loss of cell or lineage identity and gain of characteristics of neural cells. I also discuss cancer EMT, a concept having been under intense debate, and possibly the true meaning of EMT in cancer initiation and development. This synthesis provides fresh insights into a unified explanation for and a previously unrecognized nature of tumorigenesis, which might not be revealed by studies on individual molecular events. The review will also present some brief suggestions for cancer research based on the proposed model of tumorigenesis.     

Chemotherapy not only enriches but also induces cancer stem cells

Cancer stem cells are regarded as the hurdle of cancer therapy at least partially due to their intrinsic resistance to therapy. To this end, chemotherapy is widely used for enrichment of cancer stem cells. In contrast to the dogma, we hypothesized that besides enrichment, cancer stem cells could also be induced by chemotherapy in those regions without sufficient drug delivery. Due to the imbalance of the angiogenesis and insufficient blood supply in certain regions of the tumor mass, chemotherapy delivery is compromised in these regions. The insufficient drug delivery in turn transforms the bulk cancer cells to stem cells rather than kill them through NFkappaB-HIF, NFkappaB-Wnt and other signals. Detection of the induction of cancer stem cells from the chemotherapy treated non-stem cancer cells would shed light on our hypothesis, which in turn would broad our understanding of clinical cancer chemotherapy.     

Bringing Down Cancer Aircraft: Searching for Essential Hypomutated Proteins in Skin Melanoma

We propose an approach to detection of essential genes/proteins required for cancer cell survival. A gene is considered essential if a mutation with high impact upon the function of encoded protein causes death of the cancer cell. We draw an analogy between essential cancer proteins and well-known Abraham Wald’s work on estimating the plane critical areas using data on survivability of aircraft encountering enemy fire. Wald reasoned that parts with no bullet holes on the airplanes returned to the airbase from a combat flight are the most crucial ones for the airplane functioning: a hit in one of these parts downs an airplane, so it does not return back for the survey. We have envisaged that the airplane surface is a cancer genome and the bullets are somatic mutations with high impact upon protein function. Similarly we propose that genes specifically essential for tumor cell survival should carry less high-impact mutations in cancer cells compared to polymorphisms found in normal cells. We used data on mutations from the Cancer Genome Atlas and polymorphisms found in healthy humans (from 1000 Genomes Project) to predict 91 protein-coding genes essential for melanoma. These genes were selected according to several criteria, including negative selection, expression in melanocytes and decrease in the proportion of high-impact mutations in cancer compared with normal cells. The Gene Ontology analysis revealed enrichment of essential proteins related to membrane and cell periphery. We speculate that this could be a sign of immune system-driven negative selection of cancer neo-antigens. Another finding is the overrepresentation of semaphorin receptors, which can mediate distinctive signaling cascades and are involved in various aspects of tumor development. Cytokine receptors CCR5 and CXCR1 were also identified as cancer essential proteins and this is confirmed by other studies. Overall, our goal was to illustrate the idea of detecting proteins whose sequence integrity and functioning is important for cancer cell survival. Hopefully, this prediction of essential cancer proteins may point to new targets for anti-tumor therapies.     

Type I interferons induced by radiation therapy mediate recruitment and effector function of CD8+ T cells

The need for an intact immune system for cancer radiation therapy to be effective suggests that radiation not only acts directly on the tumor but also indirectly, through the activation of host immune components. Recent studies demonstrated that endogenous type I interferons (type I IFNs) play a role in radiation-mediated anti-tumor immunity by enhancing the ability of dendritic cells to cross-prime CD8⁺ T cells. However, it is still unclear to what extent endogenous type I IFNs contribute to the recruitment and function of CD8⁺ T cells. Little is also known about the effects of type I IFNs on myeloid cells. In the current study, we demonstrate that type I and type II IFNs (IFN-γ) are both required for the increased production of CXCL10 (IP-10) chemokine by myeloid cells within the tumor after radiation treatment. Radiation-induced intratumoral IP-10 levels in turn correlate with tumor-infiltrating CD8⁺ T cell numbers. Moreover, type I IFNs promote potent tumor-reactive CD8⁺ T cells by directly affecting the phenotype, effector molecule production, and enhancing cytolytic activity. Using a unique inducible expression system to increase local levels of IFN-α exogenously, we show here that the capacity of radiation therapy to result in tumor control can be enhanced. Our preclinical approach to study the effects of local increase in IFN-α levels can be used to further optimize the combination therapy strategy in terms of dosing and scheduling, which may lead to better clinical outcome.     

Heterochromatin and its Relationship to Cell Senescence and Cancer Therapy

Our goal is to understand the impact of chromatin structure on cell proliferation, cell and tissue aging, cancer and cancer therapies. To this end, we have investigated the formation of specialized domains of facultative heterochromatin, called Senescence Associated Heterochromatin Foci (SAHF), in senescent human cells. A complex of histone chaperones, HIRA and ASF1a, drives formation of SAHF. Remarkably, although SAHF are highly compacted domains of heterochromatin, these domains of facultative heterochromatin largely exclude other domains of chromatin at telomeres and pericentromeres, which are themselves thought to be constitutively heterochromatic. The relationship between SAHF formation and these other domains of heterochromatin is discussed. Also, in the course of our studies, we have obtained evidence that points to a novel function for the widely-studied but poorly-understood family of heterochromatin proteins, HP1 proteins. We propose that HP1 proteins are essential components of a dynamic nuclear response that senses and rectifies defects in epigenetic information, encoded in chromatin through histone modifications and DNA methylation. We further propose that defects in this essential "chromatin repair" response in transformed human cells contributes to the preferential killing of cancer cells by the epigenetic cancer therapies that are currently in clinical development.     

Linking alpha-synuclein properties with oxidation: a hypothesis on a mechanism underling cellular aggregation

α-Synuclein is a small, natively unstructured protein with propensity to aggregate. α-Synuclein fibrils are major components of Lewy bodies that are hallmarks of many neurodegenerative diseases. The solution properties and aggregation behavior of α-synuclein has been well characterized, but despite numerous studies that address the role of α-synuclein in cells, a clear physiological function of this protein remains a mystery. Over a hundred review articles of α-synuclein have been written in the last decade, making it difficult to list all of the important studies that have added to our insight of α-synuclein physiology. Instead, we briefly review the status of α-synuclein research and propose a model based on the idea that α-synuclein may not have an intrinsic activity in cells but rather, it modifies the function of a group of protein partners that in turn affect cell processes. We propose that it is the loss of its cellular partners under oxidative conditions that promotes α-synuclein aggregation accelerating neuronal death.     

Antiestrogenic and anticancer activities of peptides derived from the active site of alpha‐fetoprotein

Cyclo[EKTOVNOGN] (AFPep), a cyclic 9‐amino acid peptide derived from the active site of alpha‐fetoprotein, has been shown to prevent carcinogen‐induced mammary cancer in rats and inhibit the growth of ER⁺ human breast cancer xenografts in mice. Recently, studies using replica exchange molecular dynamics predicted that the TOVN region of AFPep might form a dynamically stable putative Type I beta‐turn, and thus be biologically active without additional amino acids. The studies presented in this paper were performed to determine whether TOVN and other small analogs of AFPep would inhibit estrogen‐stimulated cancer growth and exhibit a broad effective‐dose range. These peptides contained nine or fewer amino acids, and were designed to bracket or include the putative pharmacophoric region (TOVN) of AFPep. Biological activities of these peptides were evaluated using an immature mouse uterine growth inhibition assay, a T47D breast cancer cell proliferation assay, and an MCF‐7 breast cancer xenograft assay. TOVN had very weak antiestrogenic activity in comparison to AFPep's activity, whereas TOVNO had antiestrogenic and anticancer activities similar to AFPep. OVNO, which does not form a putative Type I beta‐turn, had virtually no antiestrogenic and anticancer activities. A putative proteolytic cleavage product of AFPep, TOVNOGNEK, significantly inhibited E₂‐stimulated growth in vivo and in vitro over a wider dose range than AFPep or TOVNO. We conclude that TOVNO has anticancer potential, that TOVNOGNEK is as effective as AFPep in suppressing growth of human breast cancer cells, and that it does so over a broader effective‐dose range. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd.     

Regulation of lung epithelial cell morphology by cAMP-dependent protein kinase type I isozyme

Cell shape is mediated in part by the actin cytoskeleton and the actin-binding protein vinculin. These proteins in turn are regulated by protein phosphorylation. We assessed the contribution of cAMP-dependent protein kinase A isozyme I (PKA I) to lung epithelial morphology using the E10/E9 sibling cell lines. PKA I concentration is high in flattened, nontumorigenic E10 cells but low in their round E9 transformants. PKA I activity was lowered in E10 cells by stable transfection with a dominant negative RIalpha mutant of the PKA I regulatory subunit and was raised in E9 cells by stable transfection with a wild-type Calpha catalytic subunit construct. Reciprocal changes in morphology ensued. E10 cells became rounder and grew in colonies, their actin microfilaments were disrupted, and vinculin localization at cell-cell junctions was diminished. The converse occurred in E9 cells on elevating their PKA I content. Demonstration that PKA I is responsible for the dichotomy in these cellular behaviors suggests that manipulating PKA I concentrations in lung cancer would provide useful adjuvant therapy.