Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss-of-function mutations in Patched (Ptch1) are implicated in constitutive activation of the Sonic hedgehog pathway in human basal cell carcinomas (BCCs), and inherited Ptch1 mutations underlie basal cell nevus syndrome in which a typical feature is multiple BCC occurring with greater incidence in portals of radiotherapy. Mice in which one copy of Ptch1 is inactivated show increased susceptibility to spontaneous tumor development and hypersensitivity to radiation-induced tumorigenesis, providing an ideal in vivo model to study the typical pathologies associated with basal cell nevus syndrome. We therefore examined BCC development in control and irradiated Ptch1(neo67/+) mice. We show that unirradiated mice develop putative BCC precursor lesions, i.e., basaloid hyperproliferation areas arising from both follicular and interfollicular epithelium, and that these lesions progress to nodular and infiltrative BCCs only in irradiated mice. Data of BCC incidence, multiplicity, and latency support the notion of epidermal hyperproliferations, nodular and infiltrative BCC-like tumors representing different stages of tumor development. This is additionally supported by the pattern of p53 protein expression observed in BCC subtypes and by the finding of retention of the normal remaining Ptch1 allele in all nodular, circumscribed BCCs analyzed compared with its constant loss in infiltrative BCCs. Our data suggest chronological tumor progression from basaloid hyperproliferations to nodular and then infiltrative BCC occurring in a stepwise fashion through the accumulation of sequential genetic alterations.
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PMID:Basal cell carcinoma and its development: insights from radiation-induced tumors in Ptch1-deficient mice. 1487 23

Stem cells possess two basic characteristics: they are able to renew themselves and to develop into different cell types. The link between normal stem cells and tumor cells could be examined in three aspects: what are the differences and similarities in the control of self-renewal capacity between stem cells and tumor cells; whether tumor cells arise from stem cells; do tumorous stem cells exist? Since tumor cells also exhibit self-renewal capacity, it seems plausible that their regulation is similar to that of the stem cells. The infinite self-renewal ability (immortalization) is assured by several, so far only partly known, mechanisms. One of these is telomerase activity, another important regulatory step for survival is the inhibition of apoptosis. Other signal transduction pathways in stem cell regulation may also play certain roles in carcinogenesis: e.g. Notch, Sonic hedgehog (SHH), and Wnt signals. Existence of tumor stem cells was suggested since it is simpler to retain the self-renewal capacity than to reactivate the immortality program in an already differentiated cell. Moreover, stem cells live much longer than the differentiated ones, and so they are exposed for a long period of time to impairments, collecting gene errors leading to the breakdown of the regulation. However, it is still an open question whether all cells in the tumor possess the capacity that produces this tissue or not, that is: are there tumor stem cells or there are not. If tumor stem cells exist, they would be the main target for therapy: only these must be killed since the other tumor cells possess limited proliferative capacity, therefore limited life span. The only problem is that during tumor progression stem-like cells can develop continuously and the identification but mainly the prevention of their formation is still a great challenge.
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PMID:Tumor stem cells. 1518 21

In this study, we report on recent advances on the functions of embryonic, fetal, and adult stem cell progenitors for tissue regeneration and cancer therapies. We describe new procedures for derivation and maturation of these stem cells into the tissue-specific cell progenitors. The localization of the adult stem cells and their niches, as well as their implication in the tissue repair after injuries and during cancer progression, are also described. The emphasis is on the interactions among certain developmental signaling factors, such as hormones, epidermal growth factor, hedgehog, Wnt/beta-catenin, and Notch. These factors and their pathways are involved in the stringent regulation of the self-renewal and/or differentiation of adult stem cells. Novel strategies for the treatment of both diverse degenerating disorders, by cell replacement, and some metastatic cancer types, by molecular targeting multiple tumorigenic signaling elements in cancer progenitor cells, are also illustrated.
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PMID:Concise review: recent advances on the significance of stem cells in tissue regeneration and cancer therapies. 1679 64

Runx2-Cbfa1, a Runt transcription factor, plays important roles during skeletal development. In its absence, chondrocyte hypertrophy is severely impaired and there is no vascularization of cartilage templates during skeletal development. In addition, Indian hedgehog (Ihh) signaling molecules control the space and timing of chondrocyte differentiation. Our goal was to gain a better understanding of the molecular process underlying the development of chondrosarcoma and to investigate whether there is a biological difference among variable types of chondrosarcomas. To accomplish this we collected a series of 10 enchondromas and 57 chondrosarcomas (conventional, n = 17; mesenchymal, n = 20; clear cell, n = 20), and investigated the expression of Runx2 and Ihh in these cartilaginous tumors by immunohistochemistry. Cellular and matrix-rich areas were evaluated separately. Runx2 was expressed in 100% of conventional, mesenchymal, and clear cell chondrosarcomas, and in 30% of enchondromas. Higher levels of expression of Runx2 were found in cellular areas than in matrixrich areas. Expression levels increased with increasing histological grade in conventional chondrosarcoma, suggesting involvement in tumor progression. Ihh was expressed in 100% of conventional and clear cell chondrosarcomas, especially in matrix-rich areas. Mesenchymal chondrosarcomas revealed only focal expression of Ihh in matrix-rich areas. Small cell areas were negative. Ihh was absent or focally expressed in enchondromas. These findings demonstrate that Runx2 expression is active in variable chondrosarcomas compared to enchondromas, suggesting its importance in growth and differentiation of neoplastic cartilage. Ihh expression is considered a marker of the hypertrophic stage of differentiation in these tumor cells.
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PMID:Differential expression of runx2 and Indian hedgehog in cartilaginous tumors. 1738 86

This review will highlight the significance of three critical pathways in developmental biology and our emerging understanding of their roles in regulating tumor metastasis: Bone morphogenic protein (BMP), Notch and Sonic hedgehog (SHH). We will discuss parallels between their known roles in development and how these processes can be used by tumor cells to create microenvironments that enhance tumor metastasis. That tumor cells usurp pathways critical to the developing embryo is not surprising, as many of the normal developmental programs include processes that are also seen during tumor progression to a metastatic phenotype, including epithelial to mesenchymal transition (EMT), tissue specific morphogenesis, cellular motility and invasion. BMPs are involved in EMT, contribute to tissue specific morphogenesis, and are expressed in highly-metastatic tumor cells. BMPs have also been hypothesized to have a role in the establishment of a pre-neoplastic niche. Notch and SHH facilitate neovascularization, angiogenesis, EMT and can contribute to the maintenance of highly-metastatic tumor stem cells.
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PMID:Cancer metastasis facilitated by developmental pathways: Sonic hedgehog, Notch, and bone morphogenic proteins. 1791 43

Overcoming intrinsic and acquired resistance of cancer stem/progenitor cells to current clinical treatments represents a major challenge in treating and curing the most aggressive and metastatic cancers. This review summarizes recent advances in our understanding of the cellular origin and molecular mechanisms at the basis of cancer initiation and progression as well as the heterogeneity of cancers arising from the malignant transformation of adult stem/progenitor cells. We describe the critical functions provided by several growth factor cascades, including epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor (SCF) receptor (KIT), hedgehog and Wnt/beta-catenin signalling pathways that are frequently activated in cancer progenitor cells and are involved in their sustained growth, survival, invasion and drug resistance. Of therapeutic interest, we also discuss recent progress in the development of new drug combinations to treat the highly aggressive and metastatic cancers including refractory/relapsed leukaemias, melanoma and head and neck, brain, lung, breast, ovary, prostate, pancreas and gastrointestinal cancers which remain incurable in the clinics. The emphasis is on new therapeutic strategies consisting of molecular targeting of distinct oncogenic signalling elements activated in the cancer progenitor cells and their local microenvironment during cancer progression. These new targeted therapies should improve the efficacy of current therapeutic treatments against aggressive cancers, and thereby preventing disease relapse and enhancing patient survival.
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PMID:Recent advances in cancer stem/progenitor cell research: therapeutic implications for overcoming resistance to the most aggressive cancers. 1797 79

During development, Sonic hedgehog (Shh) regulates the proliferation of cerebellar granule neuron precursors (GNPs) in part via expression of Nmyc. Mutations in the Shh signaling pathway lead to brain tumors in mice and humans. We have recently identified a novel role for the Mad family member Mad3 in GNP proliferation and Nmyc expression. Interestingly, Mad3 expression is upregulated in mouse models of medulloblastoma, the most common brain tumor in children. These results are surprising because current models suggest that Mad proteins should antagonize Myc proteins by competition for direct DNA binding via Max heterodimerization to inhibit cellular proliferation and potentially tumor progression. Here, we discuss our recent work in the context of candidate Mad3-interacting proteins and Mad3 expression in human brain tumors that together suggest interesting insights into the role of Mad3 in cellular proliferation and tumorigenesis.
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PMID:From cerebellar proliferation to tumorigenesis: new insights into the role of Mad3. 1823 19

Studying the early stages of cancer can provide important insight into the molecular basis of the disease. We identified a preneoplastic stage in the patched (ptc) mutant mouse, a model for the brain tumor medulloblastoma. Preneoplastic cells (PNCs) are found in most ptc mutants during early adulthood, but only 15% of these animals develop tumors. Although PNCs are found in mice that develop tumors, the ability of PNCs to give rise to tumors has never been demonstrated directly, and the fate of cells that do not form tumors remains unknown. Using genetic fate mapping and orthotopic transplantation, we provide definitive evidence that PNCs give rise to tumors, and show that the predominant fate of PNCs that do not form tumors is differentiation. Moreover, we show that N-myc, a gene commonly amplified in medulloblastoma, can dramatically alter the fate of PNCs, preventing differentiation and driving progression to tumors. Importantly, N-myc allows PNCs to grow independently of hedgehog signaling, making the resulting tumors resistant to hedgehog antagonists. These studies provide the first direct evidence that PNCs can give rise to tumors, and demonstrate that identification of genetic changes that promote tumor progression is critical for designing effective therapies for cancer.
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PMID:N-myc alters the fate of preneoplastic cells in a mouse model of medulloblastoma. 1917 80

Published data on hedgehog (Hh) pathway activation in colorectal cancer (CRC) are conflicting, and the effect of the Hh pathway inhibitor on the viability of colon cancer cells is controversial. This article focuses attention on the often-neglected, yet likely, critical role of Indian Hh in the course of colonic tumor progression and hypothesizes that upregulation of Indian Hh expression may offer a novel therapeutic approach against CRC through inducing differentiation of tumor cells and through abrogating the Sonic Hh signaling that drives CRC growth.
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PMID:Indian hedgehog, a neglected member of hedgehog pathway, may offer a novel avenue for colorectal cancer therapy. 1995 98

Wnt/beta-catenin signaling has been implicated in taste papilla development; however, its role in epithelial maintenance and tumor progression in the adult tongue remains elusive. We show Wnt/beta-catenin pathway activation in reporter mice and by nuclear beta-catenin staining in the epithelium and taste papilla of adult mouse and human tongues. beta-Catenin activation in APC(min/+) mice, which carry a mutation in adenomatous poliposis coli (APC), up-regulates Sonic hedgehog (Shh) and Jagged-2 (JAG2) in the tongue epithelium without formation of squamous cell carcinoma (SCC). We demonstrate that Shh suppresses beta-catenin transcriptional activity in a signaling-dependent manner in vitro and in vivo. A similar regulation and function was observed for JAG2, suggesting that both pathways negatively regulate beta-catenin, thereby preventing SCC formation in the tongue. This was supported by reduced nuclear beta-catenin in the tongue epithelium of Patched(+/-) mice, exhibiting dominant active Shh signaling. At the invasive front of human tongue cancer, nuclear beta-catenin and Shh were increased, suggesting their participation in tumor progression. Interestingly, Shh but not JAG2 was able to reduce beta-catenin signaling in SCC cells, arguing for a partial loss of negative feedback on beta-catenin transcription in tongue cancer. We show for the first time that the putative Wnt/beta-catenin targets Shh and JAG2 control beta-catenin signaling in the adult tongue epithelium, a function that is partially lost in lingual SCC.
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PMID:Sonic hedgehog acts as a negative regulator of {beta}-catenin signaling in the adult tongue epithelium. 2050 33


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