Telerman Amson Nature Reviews Cancer 2009 (original) (raw)
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Biological models and genes of tumor reversion: Cellular reprogramming through tpt1 /TCTP and SIAH-1
Proceedings of the National Academy of Sciences, 2002
Tumor reversion is the process by which some cancer cells lose their malignant phenotype. This study was aimed at defining some of the molecular and phenotypic properties of this process. Biological models of tumor reversion were isolated from human leukemia and breast cancer cell lines by using the H-1 parvovirus as a selective agent. Differential gene expression analysis was performed between the parental malignant cells and their revertants or alternatively between these parental cells and their SIAH-1 transfectant counterparts. These SIAH-1 transfectants have a suppressed malignant phenotype and were used as a control for a viral-free system. Two hundred sixty-three genes were found to be either activated or inhibited during the reversion process, as confirmed by Northern blot analysis or quantitative PCR. Of these, 32% were differentially expressed in all systems, irrespective of whether parvovirus-selected, SIAH-1 overexpressing, or p53 mutant or wild-type cell lines were used...
CURRENT OPINION Lessons from tumor reversion for cancer treatment
Tumor reversion is the biological process by which highly tumorigenic cells lose at great extent or entirely their malignant phenotype. The purpose of our research is to understand the molecular program of tumor reversion and its clinical application. We first established biological models of reversion, which was done by deriving revertant cells from different tumors. Secondly, the molecular program that could override the malignant phenotype was assessed. Differential gene-expression profiling showed that at least 300 genes are implicated in this reversion process such as SIAH-1, PS1, TSAP6, and, most importantly, translationally controlled tumor protein (TPT1/TCTP). Decreasing TPT1/TCTP is key in reprogramming malignant cells, including cancer stem cells.
Translationally controlled tumor protein is a target of tumor reversion
By analyzing the gene expression profile between tumor cells and revertant counterparts that have a suppressed malignant phenotype, we previously reported a significant down-regulation of translationally controlled tumor protein (TCTP) in the revertants. In the present study, we derived, by using the H1 parvovirus as a selective agent, revertants from three major solid cancers: colon, lung, and melanoma cell lines. These cells have a strongly suppressed malignant phenotype both in vitro and in vivo. The level of TCTP is decreased in most of the revertants. To verify whether inhibition of TCTP expression induces changes in the malignant phenotype, in the classical, well established model of ''flat reversion,'' v-src-transformed NIH3T3 cells were transfected with antisense TCTP. By inhibiting the expression of TCTP, the number of revertant cells was raised to 30%, instead of the reported rate for spontaneous flat revertants of 10 ؊6 . Because TCTP encodes for a histamine-releasing factor, we tested the hypothesis that inhibitors of the histaminic pathway could be effective against tumor cells. We show that some antihistaminic compounds (hydroxyzine and promethazine) and other pharmacological compounds with a related structure (including thioridazine and sertraline) kill tumor cells and significantly decrease the level of TCTP. All together, these data suggest that, with tumor reversion used as a working model, TCTP was identified as a target and drugs were selected that decrease its expression and kill tumor cells.
Proceedings of the National Academy of Sciences, 1999
We have previously described biological model systems for studying tumor suppression in which, by using H-1 parvovirus as a selective agent, cells with a strongly suppressed malignant phenotype (KS or US) were derived from malignant cell lines (K562 or U937). By using cDNA display on the K562/KS cells, 15 cDNAs were now isolated, corresponding to genes differentially regulated in tumor suppression. Of these, TSAP9 corresponds to a TCP-1 chaperonin, TSAP13 to a regulatory proteasome subunit, and TSAP21 to syntaxin 11, a vesicular trafficking molecule. The 15 cDNAs were used as a molecular fingerprint in different tumor-suppression models. We found that a similar pattern of differential regulation is shared by activation of p53, p21(Waf1), and the human homologue of Drosophila seven in absentia, SIAH-1. Because SIAH-1 is differentially expressed in the various models, we characterized it at the protein and functional levels. The 32-kDa, mainly nuclear protein encoded by SIAH-1, can induce apoptosis and promote tumor suppression. These results suggest the existence of a common mechanism of tumor suppression and apoptosis shared by p53, p21(Waf1), and SIAH-1 and involving regulation of the cellular machinery responsible for protein folding, unfolding, and trafficking.
Tumor reversion and embryo morphogenetic factors
Seminars in Cancer Biology, 2020
Several studies have shown that cancer cells can be "phenotypically reversed", thus achieving a "tumor reversion", by losing malignant hallmarks as migrating and invasive capabilities. These findings suggest that genome activity can switch to assume a different functional configuration, i.e. a different Gene Regulatory Network pattern. Indeed, once "destabilized", cancer cells enter into a critical transition phase that can be adequately "oriented" by yet unidentified morphogenetic factorsacting on both cells and their microenvironmentthat trigger an orchestrated array of structural and epigenetic changes. Such process can bypass genetic abnormalities, through rerouting cells toward a benign phenotype. Oocytes and embryonic tissues, obtained by animals and humans, display such "reprogramming" capability, as a number of yet scarcely identified embryo-derived factors can revert the malignant phenotype of several types of tumors. Mechanisms involved in the reversion process include the modification of cell-microenvironment cross talk (mostly through cytoskeleton reshaping), chromatin opening, demethylation, and epigenetic changes, modulation of biochemical pathways, comprising TCTP-p53, PI3K-AKT, FGF, Wnt, and TGF-β-dependent cascades. Results herein discussed promise to open new perspectives not only in the comprehension of cancer biology but also toward different therapeutic options, as suggested by a few preliminary clinical studies. 1. The historical background In the first decades of the XX century Waddington [1], and Needham [2] hypothesized that tumor emerges on the edge of a "morphological escape" of cells from the influence of a morphogenetic, individuation field, which become weak/distorted. Such a field, having lost its "driving" constraints (the "organizers") because of a number of reasonsincluding local immunological disorders, inflammation, hypoxia, just to mention a few [3], ends up being inadequate in assuring proper governance of the developmental processes emerging from the interplay between cells and their microenvironment. Conversely, the strength and relevance of such an individuation field can be appreciated when looking at its "regenerative" capabilities, as documented by a number of studies [4,5]. Conversely, cancer cells might be brought under control again if exposed to the influence of a particularly strong individuation field, like a phenotypically normal one. Indeed, normal stroma induced
Tumor reversion: a dream or a reality
Biomarker Research
Reversion of tumor to a normal differentiated cell once considered a dream is now at the brink of becoming a reality. Different layers of molecules/events such as microRNAs, transcription factors, alternative RNA splicing, post-transcriptional, post-translational modifications, availability of proteomics, genomics editing tools, and chemical biology approaches gave hope to manipulation of cancer cells reversion to a normal cell phenotype as evidences are subtle but definitive. Regardless of the advancement, there is a long way to go, as customized techniques are required to be fine-tuned with precision to attain more insights into tumor reversion. Tumor regression models using available genome-editing methods, followed by in vitro and in vivo proteomics profiling techniques show early evidence. This review summarizes tumor reversion developments, present issues, and unaddressed challenges that remained in the uncharted territory to modulate cellular machinery for tumor reversion tow...
The Hallmarks of Cancer Review evolve progressively from normalcy via a series of pre
malignant states into invasive cancers (Foulds, 1954). These observations have been rendered more con-Hormone Research Institute University of California at San Francisco crete by a large body of work indicating that the ge-nomes of tumor cells are invariably altered at multiple San Francisco, California 94143 † Whitehead Institute for Biomedical Research and sites, having suffered disruption through lesions as subtle as point mutations and as obvious as changes in Department of Biology Massachusetts Institute of Technology chromosome complement (e.g., Kinzler and Vogelstein, 1996). Transformation of cultured cells is itself a Cambridge, Massachusetts 02142 multistep process: rodent cells require at least two introduced genetic changes before they acquire tumorigenic competence, while their human counterparts are more After a quarter century of rapid advances, cancer re-difficult to transform (Hahn et al., 1999). Transgenic search has generated a rich and complex body of knowl-models of tumorigenesis have repeatedly supported the edge, revealing cancer to be a disease involving dy-conclusion that tumorigenesis in mice involves multiple namic changes in the genome. The foundation has been rate-limiting steps (Bergers et al., 1998; see Oncogene, set in the discovery of mutations that produce onco-1999, R. DePinho and T. E. Jacks, volume 18[38], pp. genes with dominant gain of function and tumor sup-5248–5362). Taken together, observations of human pressor genes with recessive loss of function; both cancers and animal models argue that tumor develop-classes of cancer genes have been identified through ment proceeds via a process formally analogous to Dar-their alteration in human and animal cancer cells and winian evolution, in which a succession of genetic by their elicitation of cancer phenotypes in experimental changes, each conferring one or another type of growth models (Bishop and Weinberg, 1996). advantage, leads to the progressive conversion of nor-Some would argue that the search for the origin and mal human cells into cancer cells (Foulds, 1954; Nowell, treatment of this disease will continue over the next 1976). quarter century in much the same manner as it has in the recent past, by adding further layers of complexity to a scientific literature that is already complex almost An Enumeration of the Traits beyond measure. But we anticipate otherwise: those The barriers to development of cancer are embodied researching the cancer problem will be practicing a drain a teleology: cancer cells have defects in regulatory matically different type of science than we have experi-circuits that govern normal cell proliferation and homeo-enced over the past 25 years. Surely much of this change stasis. There are more than 100 distinct types of cancer, will be apparent at the technical level. But ultimately, and subtypes of tumors can be found within specific the more fundamental change will be conceptual. organs. This complexity provokes a number of ques-We foresee cancer research developing into a logical tions. How many distinct regulatory circuits within each science, where the complexities of the disease, de-type of target cell must be disrupted in order for such scribed in the laboratory and clinic, will become under-a cell to become cancerous? Does the same set of standable in terms of a small number of underlying prin-cellular regulatory circuits suffer disruption in the cells ciples. Some of these principles are even now in the of the disparate neoplasms arising in the human body? midst of being codified. We discuss one set of them in Which of these circuits operate on a cell-autonomous the present essay: rules that govern the transformation basis, and which are coupled to the signals that cells of normal human cells into malignant cancers. We sug-receive from their surrounding microenvironment within gest that research over the past decades has revealed a tissue? Can the large and diverse collection of cancer-a small number of molecular, biochemical, and cellular associated genes be tied to the operations of a small traits—acquired capabilities—shared by most and per-group of regulatory circuits? haps all types of human cancer. Our faith in such simplifi-We suggest that the vast catalog of cancer cell geno-cation derives directly from the teachings of cell biology types is a manifestation of six essential alterations in cell that virtually all mammalian cells carry a similar molecu-physiology that collectively dictate malignant growth lar machinery regulating their proliferation, differentia-(Figure 1): self-sufficiency in growth signals, insensitivity tion, and death. to growth-inhibitory (antigrowth) signals, evasion of pro-Several lines of evidence indicate that tumorigenesis grammed cell death (apoptosis), limitless replicative in humans is a multistep process and that these steps potential, sustained angiogenesis, and tissue invasion reflect genetic alterations that drive the progressive and metastasis. Each of these physiologic changes— transformation of normal human cells into highly malig-novel capabilities acquired during tumor development— nant derivatives. Many types of cancers are diagnosed represents the successful breaching of an anticancer in the human population with an age-dependent inci-defense mechanism hardwired into cells and tissues. dence implicating four to seven rate-limiting, stochastic We propose that these six capabilities are shared in events (Renan, 1993). Pathological analyses of a number common by most and perhaps all types of human tu-of organ sites reveal lesions that appear to represent mors. This multiplicity of defenses may explain why cancer is relatively rare during an average human lifetime. the intermediate steps in a process through which cells