Effect of oncogenes on stem cells

Stem cells may have a special importance in the neoplastic behavior of certain lineages as well as in the normal development of these tissues. The role of oncogenes, and their normal cellular analogues, in stem cell behavior is therefore of special interest. This review describes recent results on the effects of virally-mediated src-gene transfer into hemopoietic stem cells in the physiological and developmental properties of these cells.     

How do mutated oncogenes and tumor suppressor genes cause cancer?

In recent decades we have been given insight into the process that transforms a normal cell into a malignant cancer cell. It has been recognised that malignant transformation occurs through successive mutations in specific cellular genes, leading to the activation of oncogenes and inactivation of tumor suppressor genes. The further study of these genes has generated much of its excitement from the convergence of experiments addressing the genetic basis of cancer, together with cellular pathways that normally control important cellular regulatory programmes. In the present review the context in which oncogenes such as proliferation, cell death/apoptosis, differentiation and senescence will be described, as well as how these cellular programmes become deregulated in cancer due to mutations.     

Transformation effector and suppressor genes.

Much has been learned about the molecular basis of cancer from the study of the dominantly acting viral and cellular oncogenes and their normal progenitors, the proto-oncogenes. More recent studies have resulted in the isolation and characterization of several genes prototypic of a second class of cancer genes. Whereas oncogenes act to promote the growth of cells, members of this latter class of genes act to inhibit cellular growth and are believed to contribute to the tumorigenic phenotype only when their activities are absent. This new class of cancer genes is referred to by a number of different names including; anti-oncogenes, recessive oncogenes, growth suppressor genes, tumor suppressor genes and emerogenes. Although only a few of these cancer genes have been identified, to date, it is likely that many additional genes of this class await identification. A third class of genes, necessary for the development of the cancer phenotype, is comprised of the transformation effector genes. These are normal cellular genes that encode proteins that cooperate with or activate oncogene functions and thereby induce the development of the neoplastic phenotype. The inactivation of transformation effector functions would therefore inhibit the ability of certain dominantly acting oncogenes to transform cells. The approaches outlined here describe functional assays for the isolation and molecular characterization of transformation effector and suppressor genes.     

The use of transgenic mice in unraveling the multistep process of tumorigenesis

Summary The development of cancer has long been perceived to be a complex and multistep process in which a normal cell progresses to a fully malignant tumor cell in a step-by-step fashion. At the molecular level it is believed that these steps correspond to the acquisition of activated oncogenes or alternatively the inactivation of tumor suppressor genes. With the ability to stably transfer foreign genetic information into the germ line of animals a new powerful tool to study oncogenes became available.     

Progression of colorectal cancer is associated with multiple tumor suppressor gene defects but inhibition of tumorigenicity is accomplished by correction of any single defect via chromosome transfer.

Carcinogenesis is a multistage process that has been characterized both by the activation of cellular oncogenes and by the loss of function of tumor suppressor genes. Colorectal cancer has been associated with the activation of ras oncogenes and with the deletion of multiple chromosomal regions including chromosomes 5q, 17p, and 18q. Such chromosome loss is often suggestive of the deletion or loss of function of tumor suppressor genes. The candidate tumor suppressor genes from these regions are, respectively, MCC and/or APC, p53, and DCC. In order to further our understanding of the molecular and genetic mechanisms involved in tumor progression and, thereby, of normal cell growth, it is important to determine whether defects in one or more of these loci contribute functionally in the progression to malignancy in colorectal cancer and whether correction of any of these defects restores normal growth control in vitro and in vivo. To address this question, we have utilized the technique of microcell-mediated chromosome transfer to introduce normal human chromosomes 5, 17, and 18 individually into recipient colorectal cancer cells. Additionally, chromosome 15 was introduced into SW480 cells as an irrelevant control chromosome. While the introduction of chromosome 17 into the tumorigenic colorectal cell line SW480 yielded no viable clones, cell lines were established after the introduction of chromosomes 15, 5, and 18. Hybrids containing chromosome 18 are morphologically similar to the parental line, whereas those containing chromosome 5 are morphologically distinct from the parental cell line, being small, polygonal, and tightly packed. SW480-chromosome 5 hybrids are strongly suppressed for tumorigenicity, while SW480-chromosome 18 hybrids produce slowly growing tumors in some of the animals injected. Hybrids containing the introduced chromosome 18 but was significantly reduced in several of the tumor reconstitute cell lines. Introduction of chromosome 5 had little to no effect on responsiveness, whereas transfer ot chromosome 18 restored responsiveness to some degree. Our findings indicate that while multiple defects in tumor suppressor genes seem to be required for progression to the malignant state in colorectal cancer, correction of only a single defect can have significant effects in vivo and/or in vitro.     

Growth regulation by oncogenes--new insights from model organisms

A great deal of work has focused on how oncogenes regulate the cell cycle during normal development and in cancer, yet their roles in regulating cell growth have been largely unexplored. Recent work in several model organisms has demonstrated that homologs of several oncogenes regulate cell growth and has suggested that some of the effects of oncogenes on the cell cycle may be a result of growth promotion. These studies have also suggested how growth and cell-cycle progression may be coupled.     

Oncogenes and oncogene products in urogenital cancer cells

Recent development in microbiology and genetic engineering has provided the identification and characterization of so-called 'oncogenes'. The concept of oncogenes has much stimulated intense interest in searching the cause of uncontrolled cell growth and factors responsible for formation of tumors. Because of the fact that oncogenes were first discovered in an established cell line derived from patient with bladder tumor, the association between oncogenes and genitourinary cancer has much attention. Variety of pathways of tumor development in bladder cancer can be divided in two major forms, low grade papillary tumor and high grade infiltrating tumor. Activation and a sequence of oncogenes may be relevant to the ultimate expression of these separate pathways. Concept of initiation and promotion may also be factored into these consideration. The application of these principles to the different pathways of tumor development such as in bladder, kidney and prostate cancers, supports the concept that oncogenes may be required to production of malignant tumors. The purpose of this paper is to review recent evidence that has enhanced our understanding of the genetic basis of cancer development in the genitourinary tract cancer.     

The DNA Damage Signaling Pathway Connects Oncogenic Stress to Cellular Senescence

The mechanisms of tumor suppression must be linked to the oncogenic threats that may affect a normal cell. An important cancer causing mechanism is the accidental activation of genes that stimulate cell proliferation (oncogenes) by a variety of endogenous or environmental mutagens. This event has been experimentally modelled by enforcing the expression of oncogenes in primary cells. The astonishing outcome of these manipulations is that oncogenes trigger antiproliferative responses preventing progression to malignant transformation. These responses bring to an end proliferation due to cell death or a permanent cell cycle arrest called senescence. Here we review evidence indicating that oncogene induced senescence (OIS) involves activation of p53 via the DNA damage response (DDR). These results imply mechanisms of DNA damage in cells expressing oncogenes, that may be secondary to reactive oxygen species and/or some form of “oncogenic stress” that affect normal DNA replication. Interestingly, DNA damage signals persist in cells that escape from senescence. The implications of these signals for tumorigenesis are also discussed. Given that DNA damage signals have now been observed in cells treated with any stimuli known to induce senescence, the process can be redefined as a metabolically viable but permanent cell cycle arrest with persistent DNA damage signaling.     

Activated v-myc and v-ras oncogenes do not transform normal human lymphocytes.

Activated v-myc (pSV v-myc) and v-Ha-ras (GT10) oncogenes were introduced into normal human lymphocytes, NIH 3T3 fibroblasts, B-lymphoblastoid cells, and human epithelial cells, using a reconstituted Sendai virus envelope-mediated gene transfer technique. Efficient transfer of the plasmid in each cell type was demonstrable within 1.5 h of transfection by Southern blotting of extrachromosomal DNA extracts, which unexpectedly revealed that v-myc plasmid DNA was unstable in normal lymphocytes but not in the other cell types. The v-myc plasmid was stabilized when cotransfected into lymphocytes together with v-Ha-ras. The transfected v-Ha-ras plasmid was stable in all the cell types tested. v-myc plasmid expression was clearly detectable by 5 h in all cell types except human lymphocytes. Lymphocytes expressed v-myc when transfected together with v-Ha-ras. Transfected ras oncogene was efficiently expressed in all the cell types tested. Expression of the transfected genes increased at 24 and 48 h after transfection. Even though plasmid stability and expression were achieved in myc-ras-cotransfected lymphocytes, no effects on cellular DNA synthesis or immortalization were observed, in contrast to efficient transformation of NIH 3T3 fibroblasts by the same procedure. Our data suggest that efficient expression of transfected myc and ras oncogenes in normal quiescent human lymphocytes is not sufficient for the induction of cell growth and immortalization.     

Function of oncogenes in cancer development: a changing paradigm

Tumour‐associated oncogenes induce unscheduled proliferation as well as genomic and chromosomal instability. According to current models, therapeutic strategies that block oncogene activity are likely to selectively target tumour cells. However, recent evidences have revealed that oncogenes are only essential for the proliferation of some specific tumour cell types, but not all. Indeed, the latest studies of the interactions between the oncogene and its target cell have shown that oncogenes contribute to cancer development not only by inducing proliferation but also by developmental reprogramming of the epigenome. This provides the first evidence that tumorigenesis can be initiated by stem cell reprogramming, and uncovers a new role for oncogenes in the origin of cancer. Here we analyse these evidences and propose an updated model of oncogene function that can explain the full range of genotype–phenotype associations found in human cancer. Finally, we discuss how this vision opens new avenues for developing novel anti‐cancer interventions.     

Role of growth factors and their receptors in the control of normal cell proliferation and cancer

Polypeptide growth factors modulate proliferation of nontransformed cells in vivo and in vitro, while cancer appears to reflect an alteration of growth-regulatory mechanisms found in normal cells. Some provocative clues for understanding the cellular biochemical events involved in growth regulation have come from the study of transforming retroviral oncogenes. Some of these oncogenes encode proteins similar to those implicated in growth factor-mediated growth control. Of particular interest is the study of growth factor receptors present on the cell surface, which are cellular homologs of members of the largest class of oncogenes, the tyrosine kinases. It is likely that the study of the interplay of growth factors, and the molecular basis of pleiotropic effects elicited by growth factors, will help to explain how growth factor-signaling pathways affect gene expression and cell division in normal and transformed states.     

Oncogenes and mitotic regulators: a change in perspective of our view of neoplastic processes

Our vision of the cancer cell has dramatically changed since the discovery of proto-oncogenes, whose deregulation was proposed to mimic normal growth signalling. This notion, linking cancer to cell signalling pathways, has progressively led the way to the concept of the mutator phenotype, in which genetic instability plays an essential role in the onset of cancer. This then transformed cancer into a DNA repair disease. However, as foreseen decades ago by cytogeneticists, point mutations are not sufficient to give a full picture of the whole process. As a result, aneuploidy, rather than gene mutation, has been proposed as the explanation for the complex changes observed in cancer cells. The culprits were found among genes involved in the control of the cell division cycle, and work aimed at understanding the regulation of S phase and mitosis have yielded new insights into our understanding of cancer.     

DNA Replication Licensing Factors: Novel Targets for Cancer Therapy via Inhibiting the Stemness of Cancer Cells

The replication licensing factors strictly regulate the DNA replication origin licensing process to guarantee the stability of the genome. Numerous experimental studies have recently demonstrated that the replication licensing factors as oncogenes are essential for the occurrence and development of cancers. Drug resistance, being one of the main characteristics of cancer stem cells, can cause a high recurrence rate and a low survival rate in patients with different cancers. However, the function of the replication licensing factors in cancer stemness remains unclear. The following article highlights the most recent research on DNA replication origin licensing factors in cancer and their function in anti-cancer drug resistance. Moreover, this article proposes a new perspective that replication licensing factors as chemotherapy shield affect anti-cancer drug resistance by promoting the stemness of cancer cells.     

Modulation of intercellular communication during radiation and chemical carcinogenesis

Carcinogenesis is a multistep process, involving the irreversible conversion of a stem cell to a terminal-differentiation-resistant cell ("initiation"), followed by the clonal expansion of this cell ("promotion") and by the acquisition of other genetic alterations leading to malignancy ("progression"). The initiation and progression steps seem to be facilitated by mutagenesis. Promotion has been associated with agents and conditions that cause mitogenesis. Gap junctional intercellular communication, a fundamental biological process regulating cell growth and differentiation, has been postulated to play a major role in carcinogenesis. The hypothesis is supported by the fact that many cancer cells have some dysfunction in gap junctional intercellular communication, many tumor-promoting chemicals and several oncogenes (i.e., ras, src, mos, neu, but not myc) reduce gap junctional intercellular communication, and several growth factors (i.e., EGF, TGF-beta, bovine pituitary extract) inhibit gap junction function. This integrative concept postulates that chemical promoters, oncogenes coding for growth factors, receptors, or transmembrane signaling elements, and growth factors can isolate an initiated cell from the suppressing influence of surrounding normal cells by down-regulating the transfer of ions and small molecules through gap junctions.     

Apoptosis in skin cancer development and regression

Non-melanoma skin cancers (NMSC) are the most common malignant tumors in white population and their incidence has been increasing worldwide. Molecular events regulating cell survival, apoptosis, growth arrest as well as cell differentiation, are important contributors to the overall kinetics of benign and malignant cell growth and play a role in their development, progression and regression. Failure of these pathways can result in the loss of control over proliferation and lead to tumor development through the inactivation of tumor suppressor genes or the activation of oncogenes. Also, immunological mechanisms have been implicated in a phenomenon of tumor progression as well as spontaneous tumor regression. We have tried to summarize the main events in etiopatogenesis, development, progression and in some cases skin cancer regression. Further studies are needed to elucidate completely the details of apoptotic control in normal skin and determine factors resulting in apoptotic disbalance and disease.     

Immunotherapy of prostate cancer: should we be targeting stem cells and EMT?

Cancer stem cells have been implicated in a number of solid malignancies including prostate cancer. In the case of localised prostate cancer, patients are often treated with surgery (radical prostatectomy) and/or radiotherapy. However, disease recurrence is an issue in about 30% of patients, who will then go on to receive hormone ablation therapy. Hormone ablation therapy is often palliative in a vast proportion of individuals, and for hormone-refractory patients, there are several immunotherapies targeting a number of prostate tumour antigens which are currently in development. However, clinical responses in this setting are inconsistent, and it is believed that the failure to achieve full and permanent tumour eradication is due to a small, resistant population of cells known as ‘cancer stem cells’ (CSCs). The stochastic and clonal evolution models are among several models used to describe cancer development. The general consensus is that cancer may arise in any cell as a result of genetic mutations in oncogenes and tumour suppressor genes, which consequently result in uncontrolled cell growth. The cancer stem cell theory, however, challenges previous opinion and proposes that like normal tissues, tumours are hierarchical and only the rare subpopulation of cells at the top of the hierarchy possess the biological properties required to initiate tumourigenesis. Furthermore, where most cancer models infer that every cell within a tumour is equally malignant, i.e. equally capable of reconstituting new tumours, the cancer stem cell theory suggests that only the rare cancer stem cell component possess tumour-initiating capabilities. Hence, according to this model, cancer stem cells are implicated in both tumour initiation and progression. In recent years, the role of epithelial–mesenchymal transition (EMT) in the advancement of prostate cancer has become apparent. Therefore, CSCs and EMT are both likely to play critical roles in prostate cancer tumourigenesis. This review summarises the current immunotherapeutic strategies targeting prostate tumour antigens taking into account the need to consider treatments that target cancer stem cells and cells involved in epithelial–mesenchymal transition.