Retinoblastoma loss modulates DNA damage response favoring tumor progression

Senescence is one of the main barriers against tumor progression. Oncogenic signals in primary cells result in oncogene-induced senescence (OIS), crucial for protection against cancer development. It has been described in premalignant lesions that OIS requires DNA damage response (DDR) activation, safeguard of the integrity of the genome. Here we demonstrate how the cellular mechanisms involved in oncogenic transformation in a model of glioma uncouple OIS and DDR. We use this tumor type as a paradigm of oncogenic transformation. In human gliomas most of the genetic alterations that have been previously identified result in abnormal activation of cell growth signaling pathways and deregulation of cell cycle, features recapitulated in our model by oncogenic Ras expression and retinoblastoma (Rb) inactivation respectively. In this scenario, the absence of pRb confers a proliferative advantage and activates DDR to a greater extent in a DNA lesion-independent fashion than cells that express only HRas(V12). Moreover, Rb loss inactivates the stress kinase DDR-associated p38MAPK by specific Wip1-dependent dephosphorylation. Thus, Rb loss acts as a switch mediating the transition between premalignant lesions and cancer through DDR modulation. These findings may have important implications for the understanding the biology of gliomas and anticipate a new target, Wip1 phosphatase, for novel therapeutic strategies.     

Molecular genetics of human cancer predisposition and progression

The development of human cancer is generally thought to entail a series of events that cause a progressively more malignant phenotype. Such a hypothesis predicts that tumor cells of the ultimate stage will carry each of the events, cells of the penultimate stage will carry each of the events less the last one and so on. A dissection of the pathway from a normal cell to a fully malignant tumor may thus be viewed as the unraveling of a nested set of aberrations. In experiments designed to elucidate these events we have compared genotypic combinations at genomic loci defined by restriction endonuclease recognition site variation in normal and tumor tissues from patients with various forms and stages of cancer. The first step, inherited predisposition, is best described for retinoblastoma in which a recessive mutation of a locus residing in the 13q14 region of the genome is unmasked by aberrant, but specific, mitotic chromosomal segregation. Similar mechanisms involving the distal short arm of chromosome 17 are apparent in astrocytic tumors and the events are shared by cells in each malignancy state. DNA sequencing indicates that these events accomplish the homozygosis of mutant alleles of the p53 gene. Copy number amplification of the epidermal growth factor receptor gene occurs in intermediate and late-stage tumors whereas loss of heterozygosity for loci on chromosome 10 is restricted to the ultimate stage, glioblastoma multiforme. These results suggest a genetic approach to defining degrees of tumor progression and the locations of genes involved in the pathway as a prelude to their molecular isolation and characterization.     

Retinoblastoma tumor suppressor: where cancer meets the cell cycle

The retinoblastoma tumor suppressor gene, Rb, was the first tumor suppressor identified and plays a fundamental role in regulation of progression through the cell cycle. This review details facets of RB protein function in cell cycle control and focuses on specific questions that remain intensive areas of investigation.     

Neurotrophin receptors,tumor progression and tumor maturation

The nerve growth factor receptor TrkA was initially isolated as a transforming oncogene, trk, in which most of the extracellular receptor part is replaced by the coding sequence for a tropomyosin-encoding gene. The impact that the identification of the first neurotrophin receptor has made on the entire field of developmental neurobiology cannot be overstated. Following a brief introduction to the biology of neurotrophins and their receptors, this review will focus on oncogenic Trk in human malignant disorders, discuss putative tumorigenic involvement of Trk family members in the childhood malignancy neuroblastoma, and point out potential neurotrophin-based treatment modalities for this and other neuroendocrine tumors.     

Chemical genetics in tumor lipogenesis

Since cancer cells depend on de novo lipogenesis for energy supply, highly active membrane biosynthesis and signaling, enhanced fatty acid synthesis is a crucial characteristic of cancer cells. Hence, targeting lipogenic enzymes and signaling cascades is a very promising approach in developing innovative therapeutic agents for the fight against cancer. This review summarizes main aspects of altered fatty acid synthesis in cancer cells and emphasizes the power of chemical genetic approaches in identifying and analyzing novel anti-cancer drug candidates interfering with lipid metabolism.     

Population genetics of tumor suppressor genes

Cancer emerges when a single cell receives multiple mutations. For example, the inactivation of both alleles of a tumor suppressor gene (TSG) can imply a net reproductive advantage of the cell and might lead to clonal expansion. In this paper, we calculate the probability as a function of time that a population of cells has generated at least one cell with two inactivated alleles of a TSG. Different kinetic laws hold for small and large populations. The inactivation of the first allele can either be neutral or lead to a selective advantage or disadvantage. The inactivation of the first and of the second allele can occur at equal or different rates. Our calculations provide insights into basic aspects of population genetics determining cancer initiation and progression.     

环氧合酶-2与肿瘤发生

本文从流行病学、药理学动物模型和体外药理学三个方面列举了COX－2作为肿瘤发生限速步骤的证据,分析了COX－2促进肿瘤发生的可能机制,探讨COX－2同时表达于炎症和肿瘤的意义,最后对COX－2与肿瘤发生的研究方向进行了一些推测。     

Membrane type-matrix metalloproteinases and tumor progression

Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases that process growth factors, growth factor binding proteins, cell surface proteins, degrade extracellular matrix (ECM) components and thereby play a central role in tissue remodeling and tumor progression. Membrane-type matrix metalloproteinases (MT-MMPs) are a recently discovered subgroup of intrinsic plasma membrane proteins. Their functions have been extended from pericellular proteolysis and control of cell migration to cell signaling, control of cell proliferation and regulation of multiple stages of tumor progression including growth and angiogenesis. This review sheds light on the new functions of MT-MMPs and their inhibitors in tumor development and angiogenesis, and presents recent investigations that document their influence on various cell functions.     

Chemokines in tumor development and progression

Chemokines were originally identified as mediators of the inflammatory process and regulators of leukocyte trafficking. Subsequent studies revealed their essential roles in leukocyte physiology and pathology. Moreover, chemokines have profound effects on other types of cells associated with the inflammatory response, such as endothelial cells and fibroblasts. Thus, chemokines are crucial for cancer-related inflammation, which can promote tumor development and progression. Increasing evidence points to the vital effects of several chemokines on the proliferative and invasive properties of tumor cells. The wide range of activities of chemokines in tumorigenesis highlights their roles in tumor development and progression.     

Retinoblastoma tumor suppressor functions shared by stem cell and cancer cell strategies

Carcinogenic transformation of somatic cells resembles nuclear reprogramming toward the generation of pluripotent stem cells.These events share eternal escape from cellular senescence,continuous self-renewal in limited but certain population of cells,and refractoriness to terminal differentiation while maintaining the potential to differentiate into cells of one or multiple lineages.As represented by several oncogenes those appeared to be first keys to pluripotency,carcinogenesis and nuclear reprogramming seem to share a number of core mechanisms.The retinoblastoma tumor suppressor product retinoblastoma(RB)seems to be critically involved in both events in highly complicated manners.However,disentangling such complicated interactions has enabled us to better understand how stem cell strategies are shared by cancer cells.This review covers recent findings on RB functions related to stem cells and stem cell-like behaviors of cancer cells.     

Molecular markers of tumor initiation and progression

Of the hundreds of genes and proteins reported to be altered in human cancers, only a few are sufficiently central to warrant translation into diagnostic or therapeutic tools. Three recent developments have the potential to alter radically the discovery of molecular markers: the compendium of human genes; the advent of technologies that provide the means to identify simultaneously several known and unknown genes and proteins; and an appreciation of the critical processes involved in tumor initiation and progression.     

MUC1 与肿瘤转移的研究进展

黏蛋白1（MUC1）是一种高分子量跨膜糖蛋白,广泛分布于机体正常黏膜表面,具有多种功能。MUC1在肿瘤组织中异常表达,与肿瘤的侵袭、转移和预后密切相关,具有重要的临床应用价值。本文对MUC1的结构、功能及其在多种肿瘤转移中的研究进展进行了综述,并对其在肿瘤的临床诊断及治疗中的作用进行了展望。     

Metallothionein and zinc homeostasis during tumor progression

Zinc homeostasis was studied during the induction, growth, and methotrexate (MTX) treatment of Dark Agouti rat mammary adenocarcinomas (DAMA). A progressive fall in plasma Zn concentration (pZn), significant at a tumor burden of less than 1% body weight (bw), was sustained during tumor enlargement to give a 54% reduction in pZn at 16.3% bw (n=6/group). The hypozincemia was attributed to the increasing Zn demand for tumor growth. Zn content of the 16.3% bw tumors equaled that of muscle (normally 60% of total body Zn). Tumor metallothionein (tMT) was sufficient to bind <3% of total tumor Zn, and hepatic MT (hMT) remained at basal concentrations during early tumor growth, doubling only in the presence of significant necrosis in large tumors. Methotrexate (MTX, 0.5 mg/Kg im x 2 d) at respective tumor burdens of 5 and 10% bw (n=9, 10/group) gave 2 therapeutic effects, dependent on tumor size: 1.5% bw tumors in 7 rats remained close to their original size until experiment end when pZn, hMT, and tMT were typical of 5% bw untreated tumors. 2. Tumors in 5 rats given MTX at 10% bw had marked subcapsular necrosis and regression to a size similar to those in group 1; pZn returned toward normal, whereas hMT was 6 times its 5% bw counterpart. Host weight loss was significantly reduced, as were tumor-associated changes in plasma glucose and calcium. In summary, neither tMT nor hMT appears to play a role in the hypozincemia that follows DAMA Zn sequestration and growth. Critically timed MTX can result in tumor regression and return of plasma Zn, Ca, and glucose toward normal. This is associated with an increase in hMT and reduction in host weight loss, suggesting a flow of Zn from the resorbing tumor to the host, enabling the synthesis of hMT and retention of host structural proteins.     

Microvesicles: Messengers and mediators of tumor progression

Cellular interactions play a crucial role in progression, angiogenesis and invasiveness of tumors, including glioma. The traditionally accepted view is that medium and long-range cellular communications occur primarily through gradients of soluble ligands, recognizable by the cell-associated receptors. Recent findings, however, suggest the existence of another mode of intercellular communication, where the ‘units’ of information are microvesicles containing a multitude of biologically active protein and RNA species, including oncogenic receptors, such as EGFRvIII. Moreover, microvesicles can be retrieved from the circulating blood of cancer patients, and reveal the presence of oncogenes in their tumors, thereby potentially serving as information-rich prognostic and predictive biomarkers.