The role of stem cells and gap junctional intercellular communication in carcinogenesis

Understanding the process of carcinogenesis will involve both the accumulation of many scientific facts derived from molecular, biochemical, cellular, physiological, whole animal experiments and epidemiological studies, as well as from conceptual understanding as to how to order and integrate those facts. From decades of cancer research, a number of the "hallmarks of cancer" have been identified, as well as their attendant concepts, including oncogenes, tumor suppressor genes, cell cycle biochemistry, hypotheses of metastasis, angiogenesis, etc. While all these "hallmarks" are well known, two important concepts, with their associated scientific observations, have been generally ignored by many in the cancer research field. The objective of the short review is to highlight the concept of the role of human adult pluri-potent stem cells as "target cells" for the carcinogenic process and the concept of the role of gap junctional intercellular communication in the multi-stage, multi-mechanism process of carcinogenesis. With these two concepts, an attempt has been made to integrate the other well-known concepts, such as the multi-stage, multimechanisn or the "initiation/promotion/progression" hypothesis; the stem cell theory of carcinogenesis; the oncogene/tumor suppression theory and the mutation/epigenetic theories of carcinogenesis. This new "integrative" theory tries to explain the well-known "hallmarks" of cancers, including the observation that cancer cells lack either heterologous or homologous gap junctional intercellular communication whereas normal human adult stem cells do not have expressed or functional gap junctional intercellular communication. On the other hand, their normal differentiated, non-stem cell derivatives do express connexins and express gap junctional intercellular communication during their differentiation. Examination of the roles of chemical tumor promoters, oncogenes, connexin knock-out mice and roles of genetically-engineered tumor and normal cells with connexin and anti-sense connexin genes, respectively, seems to provide evidence which is consistent with the roles of both stem cells and gap junctional communication playing a major role in carcinogenesis. The integrative hypothesis provides new strategies for chemoprevention and chemotherapy which focuses on modulating connexin gene expression or gap junctional intercellular communication in the premalignant and malignant cells, respectively.     

Role of stem cells in cancer therapy and cancer stem cells: a review

For over 30 years, stem cells have been used in the replenishment of blood and immune systems damaged by the cancer cells or during treatment of cancer by chemotherapy or radiotherapy. Apart from their use in the immuno-reconstitution, the stem cells have been reported to contribute in the tissue regeneration and as delivery vehicles in the cancer treatments. The recent concept of 'cancer stem cells' has directed scientific communities towards a different wide new area of research field and possible potential future treatment modalities for the cancer. Aim of this review is primarily focus on the recent developments in the use of the stem cells in the cancer treatments, then to discuss the cancer stem cells, now considered as backbone in the development of the cancer; and their role in carcinogenesis and their implications in the development of possible new cancer treatment options in future.     

The pioneering spirit of Takashi Sugimura: his studies of the biochemistry of poly(ADP-ribosylation) and of cancer

Takashi Sugimura has accomplished many scientific achievements in the field of biochemistry and in cancer research. Sugimura's group identified the novel polymer poly(ADP-ribose) in parallel to P. Mandel's and O. Hayaishi's groups and demonstrated the presence of the enzyme poly(ADP-ribose) polymerase (PARP). He also discovered the cognate catabolic enzyme, poly(ADP-ribose) glycohydrolase (PARG) and further elucidated the biology of poly(ADP-ribose). The astonishing discovery of pierisin, an apoptogenic peptide that ADP-ribosyaltes DNA, profoundly illuminates his scientific character and curiosity as well. Sugimura's work in cancer research shows an extraordinarily wide range, which includes the establishment of new methods in chemical carcinogenesis, the identification of various environmental mutagens/carcinogens and new tumour promoters. He also established the concept that cancer is a disease of DNA and contributed to the development of the concept of the multi-step model of carcinogenesis.     

Repair and regeneration: opportunities for carcinogenesis from tissue stem cells

This review will discuss the mechanisms of repair and regeneration in various tissue types and how dysregulation of these mechanisms may lead to cancer. Normal tissue homeostasis involves a careful balance between cell loss and cell renewal. Stem and progenitor cells perform these biologic processes as the functional units of regeneration during both tissue homeostasis and repair. The concept of tissue stem cells capable of giving rise to all differentiated cells within a given tissue led to the concept of a cellular hierarchy in tissues and in tumors. Thus, only a few cells may be necessary and sufficient for tissue repair or tumor regeneration. This is known as the hierarchical model of tumorigenesis. This report will compare this model with the stochastic model of tumorigenesis. Under normal circumstances, the processes of tissue regeneration or homeostasis are tightly regulated by several morphogen pathways to prevent excessive or inappropriate cell growth. This review presents the recent evidence that dysregulation of these processes may provide opportunities for carcinogenesis for the long-lived, highly proliferative tissue stem cell population. New findings of cancer initiating tissue stem cells identified in several solid and circulating cancers including breast, brain and hematopoietic tumors will also be reviewed. Finally, this report reviews the cellular biology of cancer and its relevance to the development of more effective cancer treatment protocols.     

New Insights into Syndecan-2 Expression and Tumourigenic Activity in Colon Carcinoma Cells

Adhesion receptors play crucial roles in the neoplastic transformation of normal cells through induction of cancer-specific cellular behaviour and morphology. This implies that cancer cells likely express and utilize a distinct set of adhesion receptors during carcinogenesis. Colon cancer is an excellent model system for the study of this process, since both molecular genetic and morphological changes have been well established for this disease. We recently reported increased expression of the cell surface adhesion receptor, syndecan-2, in several colon carcinoma cell lines. Indeed, increased syndecan-2 expression was necessary for tumourigenic activity, suggesting that syndecan-2 might have value as both a new diagnostic marker and a possible therapeutic target. Here, we review recent advances in understanding the role of syndecan-2 in the carcinogenesis of colon cells, and discuss a leading role for this molecule in a new era for colon cancer treatment.     

Model of accelerated carcinogenesis based on proliferative stress and inflammation for doses relevant to radiotherapy

Recent findings demonstrate that accelerated carcinogenesis following liver regeneration is associated with chronic inflammation-induced double-strand DNA breaks in cells, which escaped apoptosis due to proliferative stress. In this work, proliferative stress and inflammation-based carcinogenesis at large dose were included in a cancer induction model considering fractionation. At large dose, tissue injury due to irradiation could be so severe that under the regenerative proliferative stress induced by cell loss, the genomic unstable cells generated during irradiation and/or inflammation escape senescence or apoptosis and reenter the cell cycle, triggering enhanced carcinogenesis. This acceleration—modeled to be proportional to the number of repopulated cells—is only significant, however, when tissue injury is severe and thus proportional to the cell loss in the tissue. The general solutions to the resulting differential equations for carcinoma induction were computed. In case of full repopulation or acute low-dose irradiation, the acceleration term disappears from the equation describing cancer induction. The acceleration term is affecting the dose–response curve for carcinogenesis only at large doses. An example for bladder cancer is shown. An existing model for cancer induction after fractionated radiotherapy which is based on cell mutations was extended here by including the effects of inflammation and proliferative stress, and an additional model parameter was established which describes acceleration. The new acceleration parameter affects the dose–response model only at large dose and is only effective when the tissue is not capable of fully repopulating between dose fractions.     

基因突变在结直肠癌发生机制中的作用:殊途同归

结直肠癌的多步骤演进模式一直是肿瘤研究的经典,在这一过程中,序贯发生的基因突变(或其它遗传事件)是重要的推动力。本文综述了在结直肠癌中检测到的基因突变情况,并分析了在新一代测序技术的带动下,结直肠癌基因组学的最新进展。结直肠癌组织基因突变的地形图理念对于今后的肿瘤分子诊疗将具有重要意义。肿瘤不仅是基因病,更是信号通路异常病。     

Multistep carcinogenesis: a chain reaction of aneuploidizations

Carcinogenesis is a multistep process in which new, parasitic and polymorphic cancer cells evolve from a single, normal diploid cell. This normal cell is converted to a prospective cancer cell, alias "initiated", either by a carcinogen or spontaneously. The initiated cell typically does not have a new distinctive phenotype yet, but evolves spontaneously--over months to decades--to a clinical cancer. The cells of a primary cancer also evolve spontaneously towards more and more malignant phenotypes. The outstanding genotype of initiated and cancer cells is aneuploidy, an abnormal balance of chromosomes, which increases and varies in proportion with malignancy. The driving force of the spontaneous evolution of initiated and cancerous cells to ever more abnormal phenotypes is said to be their "genetic instability". However, since neither the instability of cancer phenotypes nor the characteristically slow kinetics of carcinogenesis are compatible with gene mutation, we propose here that the driving force of carcinogenesis is the inherent instability of aneuploid karyotypes. Aneuploidy renders chromosome structure and segregation error-prone, because it unbalances mitosis proteins and the many teams of enzymes that synthesize and maintain chromosomes. Thus, carcinogenesis is initiated by a random aneuploidy, which is induced either by a carcinogen or spontaneously. The resulting karyotype instability sets off a chain reaction of aneuploidizations, which generate ever more abnormal and eventually cancer-specific combinations and rearrangements of chromosomes. According to this hypothesis the many abnormal phenotypes of cancer are generated by abnormal dosages of thousands of aneuploid, but un-mutated genes.     

Multistep Carcinogenesis: A Chain Reaction of Aneuploidizations

Carcinogenesis is a multistep process in which new, parasitic and polymorphic cancer cells evolve from a single, normal diploid cell. This normal cell is converted to a prospective cancer cell, alias "initiated", either by a carcinogen or spontaneously. The initiated cell typically does not have a new distinctive phenotype yet, but evolves spontaneously—over months to decades—to a clinical cancer. The cells of a primary cancer also evolve spontaneously towards more and more malignant phenotypes. The outstanding genotype of initiated and cancer cells is aneuploidy, an abnormal balance of chromosomes, which increases and varies in proportion with malignancy. The driving force of the spontaneous evolution of initiated and cancerous cells to ever more abnormal phenotypes is said to be their "genetic instability". However, since neither the instability of cancer phenotypes nor the characteristically slow kinetics of carcinogenesis are compatible with gene mutation, we propose here that the driving force of carcinogenesis is the inherent instability of aneuploid karyotypes. Aneuploidy renders chromosome structure and segregation error-prone, because it unbalances mitosis proteins and the many teams of enzymes that synthesize and maintain chromosomes. Thus, carcinogenesis is initiated by a random aneuploidy, which is induced either by a carcinogen or spontaneously. The resulting karyotype instability sets off a chain reaction of aneuploidizations, which generate ever more abnormal and eventually cancer-specific combinations and rearrangements of chromosomes. According to this hypothesis the many abnormal phenotypes of cancer are generated by abnormal dosages of thousands of aneuploid, but un-mutated genes.     

Insight of nitric oxide signaling: A potential biomarker with multifaceted complex mechanism in colorectal carcinogenesis

Colorectal carcinogenesis (CRC) is the most important health concerns throughout the World as the tumour cells rapidly spread and abruptly grow in colon and rectum to further organs. Several etiological factors are associated with colorectal carcinogenesis. During invasion and proliferation of tumour cells, various mechanistic molecular pathways are involved in the cells. Nitric Oxide pathway (NO) is one of the important cellular mechanisms associated with tumour cells initiation, invasion and progression. Epidemiological evidences suggest that NO has potential role in development of cancer. The multidisciplinary action of NO on the initiation of cancer depends on several factors including cell type, metastasis stage, and organs involved. This review emphasizes the biological significance of NO in each step of cancer metastasis, its controversial effects for carcinogenesis including initiation, invasion and progression.     

Redox biology and gastric carcinogenesis: the role of Helicobacter pylori

Almost half the world's population is infected by Helicobacter pylori (H. pylori). This bacterium increases the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in human stomach, and this has been reported to impact upon gastric inflammation and carcinogenesis. However, the precise mechanism by which H. pylori induces gastric carcinogenesis is presently unclear. Although the main source of ROS/RNS production is possibly the host neutrophil, H. pylori itself produces O???. Furthermore, its cytotoxin induces ROS production by gastric epithelial cells, which might affect intracellular signal transduction, resulting in gastric carcinogenesis. Excessive ROS production in gastric epithelial cells can cause DNA damage and thus might be involved in gastric carcinogenesis. Understanding the molecular mechanism of H. pylori-induced carcinogenesis is important for developing new strategies against gastric cancer.     

Role of proteomics in translational research in cervical cancer

Cervical cancer is one of the leading causes of cancer morbidity and mortality in women worldwide. More than 98% of cases are related to a human papillomavirus (HPV) infection. Infection with specific subtypes of HPV has been strongly implicated in cervical carcinogenesis. The identification and functional verification of host proteins associated with HPV E6 and E7 oncoproteins may provide useful information for understanding cervical carcinogenesis and the development of cervical cancer-specific markers. In addition, proteomic profiling of altered proteins by anticancer drugs on cervical cancer cells may contribute to providing the fundamental resources for investigation of disease-specific target proteins, elucidation of the novel mechanisms of action and development of new drugs. The advent of proteomics has provided the hope of discovering novel biological markers for use in the screening, early diagnosis and prediction of response to therapy. This review describes the studies where profiles of protein expression in cervical cancer have been generated.     

Cellular and molecular effects of vitamin D on carcinogenesis

Epidemiologic data suggest that the incidence and severity of many types of cancer inversely correlates with indices of vitamin D status. The vitamin D receptor (VDR) is highly expressed in epithelial cells at risk for carcinogenesis including those resident in skin, breast, prostate and colon, providing a direct molecular link by which vitamin D status impacts on carcinogenesis. Consistent with this concept, activation of VDR by its ligand 1,25-dihydroxyvitamin D (1,25D) triggers comprehensive genomic changes in epithelial cells that contribute to maintenance of the differentiated phenotype, resistance to cellular stresses and protection of the genome. Many epithelial cells also express the vitamin D metabolizing enzyme CYP27B1 which enables autocrine generation of 1,25D from the circulating vitamin D metabolite 25-hydroxyvitamin D (25D), critically linking overall vitamin D status with cellular anti-tumor actions. Furthermore, pre-clinical studies in animal models has demonstrated that dietary supplementation with vitamin D or chronic treatment with VDR agonists decreases tumor development in skin, colon, prostate and breast. Conversely, deletion of the VDR gene in mice alters the balance between proliferation and apoptosis, increases oxidative DNA damage, and enhances susceptibility to carcinogenesis in these tissues. Because VDR expression is retained in many human tumors, vitamin D status may be an important modulator of cancer progression in persons living with cancer. Collectively, these observations have reinforced the need to further define the molecular actions of the VDR and the human requirement for vitamin D in relation to cancer development and progression.     

A mathematical model for progression and heterogeneity in colorectal cancer dynamics

This paper deals with the development of a mathematical model that describes cancer dynamics at the cellular scale.The selected case study concerns colon and rectum cancer, which originates in colorectal crypts. Cells inside the crypts are assumed to be organized according to a compartmental-like arrangement and to be homogeneously mixing. A mathematical model for cancer progression is proposed here. This model describes the generation of multiple clonal sub-populations of cells at different progression stages in a single crypt.Asymptotic analysis and simulations are developed with an exploratory aim. The obtained results offer some insights into the role played by mutation, proliferation and differentiation phenomena on cancer dynamics. In particular, the acquisition of an additional growing power and a reduction for cellular differentiation seem more likely to be the driving force behind carcinogenesis rather than an increase in the mutation rate. The mutation rate instead seems to affect progression dynamics and intra-tumor heterogeneity. The role played by cells, at different differentiation stages, in the onset and progression of colorectal cancer is highlighted. The results support the fact that stem cells play a key role in cancer development and the idea that transit-amplifying cells could also take on an active role in carcinogenesis.     

Using induced pluripotent stem cells as a tool for modelling carcinogenesis

Cancer is a highly heterogeneous group of diseases that despite improved treatments remain prevalent accounting for over 14 million new cases and 8.2 million deaths per year. Studies into the process of carcinogenesis are limited by lack of appropriate models for the development and pathogenesis of the disease based on human tissues. Primary culture of patient samples can help but is difficult to grow for a number of tissues. A potential opportunity to overcome these barriers is based on the landmark study by Yamanaka which demonstrated the ability of four factors;Oct4, Sox2, Klf4, and c-Myc to reprogram human somatic cells in to pluripotency. These cells were termed induced pluripotent stem cells(i PSCs) and display characteristic properties of embryonic stem cells. This technique has a wide range of potential uses including disease modelling, drug testing and transplantation studies. Interestingly i PSCs also share a number of characteristics with cancer cells including self-renewal and proliferation, expression of stem cell markers and altered metabolism. Recently, i PSCs have been generated from a number of human cancer cell lines and primary tumour samples from a range of cancers in an attempt to recapitulate the development of cancer and interrogate the underlying mechanisms involved. This review will outline the similarities between the reprogramming process and carcinogenesis, and how these similarities have been exploited to generate i PSC models for a number of cancers.     

肿瘤干细胞与卵巢癌研究进展

近年来,肿瘤干细胞学说作为肿瘤发生发展的重要原因获得越来越多的认可。肿瘤干细胞是指肿瘤中存在的含量极少、具有无限增殖潜能的干细胞样肿瘤细胞,它们能自我更新、分化、迁徙,是导致肿瘤发生、发展、转移和耐药的重要原因。卵巢癌也可能是卵巢癌干细胞所致的疾病。卵巢癌干细胞的分离鉴定正处于起始阶段,针对卵巢癌干细胞的靶向治疗可能在卵巢癌治疗中具有重要作用,为临床彻底治愈卵巢癌带来希望。     

New stochastic carcinogenesis model with covariates: an approach involving intracellular barrier mechanisms

In this paper we present a new multiple-pathway stochastic model of carcinogenesis with potential of predicting individual incidence risks on the basis of biomedical measurements. The model incorporates the concept of intracellular barrier mechanisms in which cell malignization occurs due to an inefficient operation of barrier cell mechanisms, such as antioxidant defense, repair systems, and apoptosis. Mathematical formalism combines methodological innovations of mechanistic carcinogenesis models and stochastic process models widely used in studying biodemography of aging and longevity. An advantage of the modeling approach is in the natural combining of two types of measures expressed in terms of model parameters: age-specific hazard rate and means of barrier states. Results of simulation studies allow us to conclude that the model parameters can be estimated in joint analyses of epidemiological data and newly collected data on individual biomolecular measurements of barrier states. Respective experimental designs for such measurements are suggested and discussed. An analytical solution is obtained for the simplest design when only age-specific incidence rates are observed. Detailed comparison with TSCE model reveals advantages of the approach such as the possibility to describe decline in risk at advanced ages, possibilities to describe heterogeneous system of intermediate cells, and perspectives for individual prognoses of cancer risks. Application of the results to fit the SEER data on cancer risks demonstrates a strong predictive power of the model. Further generalizations of the model, opportunities to measure barrier systems, biomedical and mathematical aspects of the new model are discussed.