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

Mast cells (MCs) display a diversity of roles that may contribute to the stromal microenvironment alterations during tumor progression. The aim of this study was to investigate MC populations expressing tryptase and c-kit in lip squamous cell carcinoma (lip SCC) (n=37), actinic cheilitis (AC) (n=15) and normal lip mucosa (control) (n=6), as well as their relationship with microscopic parameters (collagen degeneration, elastin changes, angiogenesis and proliferative index). Tryptase, c-kit, CD31 and Ki-67 expressions were analyzed by means of immunohistochemistry and collagen and elastic fibers were visualized with Picrosirus and Verhoeff's stain, respectively. The numbers of tryptase+ MC were significantly higher in lip SCC when compared with control (P=0.01), while a similar density of these cells was observed in AC and lip SCC (P=0.09). The density of c-kit+ MC was similar in all groups examined (P=0.65). MC migration (c-kit+/Tryptase+ relationship) was 69% in lip SCC, 60% in AC and 100% in control. The number of CD31+ blood vessels was significantly higher in the lip SCC when compared with control and AC (P<0.01). The increase of MCs and angiogenesis in lip SCC may reflect an important modification in the tumor microenvironment during squamous photo-carcinogenesis.
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PMID:Density and migration of mast cells in lip squamous cell carcinoma and actinic cheilitis. 1922 48

Emerging evidence shows that microRNAs (miR) are involved in the pathogenesis of a variety of cancers, including prostate carcinoma (PCa). Little information is available regarding miR expression levels in lymph node metastasis of prostate cancer or the potential of miRs as prognostic markers in this disease. Therefore, we analyzed the global expression of miRs in benign, hyperplastic prostate tissue (BPH), primary PCa of a high risk group of PCa patients, and corresponding metastatic tissues by microarray analysis. Consistent with the proposal that some miRs are oncomirs, we found aberrant expression of several miRs, including the downregulation of miR-221, in PCa metastasis. Downregulation of miR-221 was negatively correlated with the expression of the proto-oncogen c-kit in primary carcinoma. In a large study cohort, the prostate-specific oncomir miR-221 was progressively downregulated in aggressive forms of PCa. Downregulation of miR-221 was associated with clinicopathological parameters, including the Gleason score and the clinical recurrence during follow up. Kaplan-Meier estimates and Cox proportional hazard models showed that miR-221 downregulation was linked to tumor progression and recurrence in a high risk prostate cancer cohort. Our results showed that progressive miR-221 downregulation hallmarks metastasis and presents a novel prognostic marker in high risk PCa. This suggests that miR-221 has potential as a diagnostic marker and therapeutic target in PCa.
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PMID:Expression of microRNA-221 is progressively reduced in aggressive prostate cancer and metastasis and predicts clinical recurrence. 1958 79

Two families with a germline Asp820Tyr mutation at exon 17 of the c-kit gene and multiple gastrointestinal stromal tumors (GISTs) have been reported. Recently, we generated a knock-in mouse model of the family, and mice with KIT-Asp818Tyr corresponding to human KIT-Asp820Tyr showed a cecal GIST-like tumor. In this report, we examined the in vivo effect of imatinib on tumor progression in knock-in mice. Imatinib of 100 microg/g body weight was administered to heterozygous (KIT-Asp818Tyr/+) mice orally for 7, 14 and 28 days, and cecal tumors were dissected. Both macroscopic size and the measured volume of cecal tumors were not significantly reduced after a 7-, 14- and 28-day administration of imatinib when compared with those before imatinib administration. Cell proliferation was assessed by Ki-67 immunohistochemistry and the labeling index significantly decreased after imatinib administration, but the value of the index after imatinib was only about half compared with that before imatinib. Western blotting and real-time PCR revealed that KIT expression was almost equivalent, but KIT phosphorylation was significantly but not completely inhibited in tumor tissues after 7, 14 and 28 days of imatinib administration when compared with that before imatinib administration. Phosphorylation of Akt and Stat1 was accordingly inhibited after imatinib administration. Thus, imatinib seemed to inhibit in vivo tumor proliferation but not decrease tumor volume on this mouse model, probably because of an insufficient inhibition of phosphorylation of KIT and its downstream signaling molecules. These results suggested that progression of multiple GISTs in patients with germline Asp820Tyr might be partially controlled by imatinib and that model mice provide an opportunity to examine the effect of various other targeted drugs on in vivo tumor progression.
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PMID:In vivo effect of imatinib on progression of cecal GIST-like tumors in exon 17-type c-kit knock-in mice. 1963 92

Neurofibromatosis type 1 (NF1) is the most common genetic disorder with a predisposition to malignancy and affects 1 in 3500 persons worldwide. NF1 is caused by a mutation in the NF1 tumor suppressor gene that encodes the protein neurofibromin. Patients with NF1 have cutaneous, diffuse, and plexiform neurofibromas, tumors comprised primarily of Schwann cells, blood vessels, fibroblasts, and mast cells. Studies from human and murine models that closely recapitulate human plexiform neurofibroma formation indicate that tumorigenesis necessitates NF1 loss of heterozygosity in the Schwann cell. In addition, our most recent studies with bone marrow transplantation and pharmacologic experiments implicate haploinsufficiency of Nf1 (Nf1(+/-)) and c-kit signaling in the hematopoietic system as required and sufficient for tumor progression. Here, we review recent studies implicating the hematopoietic system in plexiform neurofibroma genesis, delineate the physiology of stem cell factor-dependent hematopoietic cells and their contribution to the neurofibroma microenvironment, and highlight the application of this research toward the first successful, targeted medical treatment of a patient with a nonresectable and debilitating neurofibroma. Finally, we emphasize the importance of the tumor microenvironment hypothesis, asserting that tumorigenic cells in the neurofibroma do not arise and grow in isolation.
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PMID:Mast cells and the neurofibroma microenvironment. 2023 71

c-Kit tyrosine kinase receptor and its ligand stem cell factor have multiple functions during development, whereas in adulthood they are mostly needed for stem cell (SC) maintenance and mast cell (MC) biology. c-Kit plays an essential tumor-cell-intrinsic role in many types of cancer, either providing the tumorigenic force when aberrantly activated or conferring stem-like features characterizing the most aggressive variants. A tumor-cell-extrinsic role occurs through c-Kit-dependent accessory cells (such as MCs) that infiltrate tumors and deeply influence their progression. c-Kit-targeted therapy with tyrosine kinase inhibitors (TKIs) may ideally work against both tumor and stromal cells. Here, we summarize the tumor-intrinsic and -extrinsic roles of c-Kit in cancer and discuss TKIs with their on- and off-targets, with a special emphasis on MCs as paradigmatic c-Kit-dependent accomplices for tumor progression.
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PMID:Tumor-intrinsic and -extrinsic roles of c-Kit: mast cells as the primary off-target of tyrosine kinase inhibitors. 2105 34

Angiogenesis plays a crucial role in tumor progression. Tumor angiogenesis is driven by host-derived circulating factors. Prominent among these factors is vascular endothelial growth factor (VEGF). Two basic approaches have been pursued in therapies targeting VEGF: neutralization of VEGF by antibodies or inhibition of VEGF receptor (VEGFR). VEGFR inhibition has relied on the use of small-molecular inhibitors. These drugs inhibit the tyrosine kinase activity of VEGFRs as well as other tyrosine kinases, and the term tyrosine kinase inhibitor (TKI) is used to describe this class of drugs. Pazopanib (GW786034), N(4)-(2,3-dimethyl-2H-indazol-6-yl]-N(4) - methyl-N(2)-(4-methyl-3-sulfnonamidophenyl)-2,4-pyrimidinediamine, is a novel orally bioavailable TKI that targets VEGFR1, VEGFR3, platelet-derived growth factor receptor (PDGFR)-alpha, PDGFR-beta and c-kit. Activity was observed in early clinical testing, specifically in patients with metastatic renal cell carcinoma (RCC). In subsequent phase II and phase III trials, the activity of pazopanib was comparable to other targeted agents used in the first-line therapy of metastatic RCC. Promising activity was reported in a number of other tumors, including metastatic carcinoma of the uterine cervix and differentiated carcinomas of the thyroid.
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PMID:Pazopanib: a new multiple tyrosine kinase inhibitor in the therapy of metastatic renal cell carcinoma and other solid tumors. 2176 86

Acquisition of homozygous activating growth factor receptor mutations might accelerate cancer progression through a simple gene-dosage effect. Internal tandem duplications (ITDs) of FLT3 occur in approximately 25% cases of acute myeloid leukemia and induce ligand-independent constitutive signaling. Homozygous FLT3-ITDs confer an adverse prognosis and are frequently detected at relapse. Using a mouse knockin model of Flt3-internal tandem duplication (Flt3-ITD)-induced myeloproliferation, we herein demonstrate that the enhanced myeloid phenotype and expansion of granulocyte-monocyte and primitive Lin(-)Sca1(+)c-Kit(+) progenitors in Flt3-ITD homozygous mice can in part be mediated through the loss of the second wild-type allele. Further, whereas autocrine FLT3 ligand production has been implicated in FLT3-ITD myeloid malignancies and resistance to FLT3 inhibitors, we demonstrate here that the mouse Flt3(ITD/ITD) myeloid phenotype is FLT3 ligand-independent.
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PMID:Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation. 2181 52

Mast cells (MC) are c-Kit-expressing cells, best known for their primary involvement in allergic reactions, but recently reappraised as important players in either cancer promotion or inhibition. Here, we assessed the role of MCs in prostate tumor development. In prostate tumors from both tumor-prone transgenic adenocarcinoma of the mouse prostate (TRAMP) mice and human patients, MCs are specifically enriched and degranulated in areas of well-differentiated (WD) adenocarcinoma but not around poorly differentiated (PD) foci that coexist in the same tumors. We derived novel TRAMP tumor cell lines, representative of WD and PD variants, and through pharmacologic stabilization or genetic ablation of MCs in recipients mice, we showed that MCs promote WD adenocarcinoma growth but are dispensable for PD tumors. WD tumors rely on MCs for matrix metalloprotease 9 (MMP-9) provision, as reconstitution of MC-deficient mice with wild-type but not MMP-9(-/-) MCs was sufficient to promote their growth. In contrast, PD tumors are MMP-9 self-competent, consistently with epithelial-to-mesenchymal transition. Such a dual source of MMP-9 was confirmed in human tumors, suggesting that MCs could be a good target for early-stage prostate cancer. Interestingly, in testing whether MC targeting could block or delay tumorigenesis in tumor-prone TRAMP mice, we observed a high incidence of early and aggressive tumors, characterized by a neuroendocrine (NE) signature and c-Kit expression. Taken together, these data underscore the contribution of MCs in tumor progression and uncover a new, opposite role of MCs in protecting against the occurrence of aggressive NE variants in prostate cancer.
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PMID:Mast cell targeting hampers prostate adenocarcinoma development but promotes the occurrence of highly malignant neuroendocrine cancers. 2189 41

Melanocytic tumors occur as much in humans as in dogs and are frequently associated with receptor tyrosine kinase dysregulation. The transmembrane c-kit protein is a receptor tyrosine kinase that is crucial in melanocytic homeostasis and, when mutated, is associated with tumor development in those cells. In human studies, its expression is generally detected in melanocytomas and primary malignant melanomas, being lost with tumor progression and metastasis. In this study, we aimed to analyze c-kit expression in canine cutaneous melanocytic tumors and its association with tumor behavior, in order to investigate the dog's potential in comparative pathology and c-kit's potential in the diagnosis of these tumors. The expression of c-kit was evaluated immunohistochemically in 39 canine cutaneous melanocytic tumors and scored in terms of the labeling location, extension, and intensity. The labeling location was essentially cytoplasmic, and the labeling extension and intensity were generally higher in melanocytomas (83.3% diffuse-labeled cells) than those in malignant melanomas (22.2% negative-labeled cells). The differences found in the labeling extension were statistically significant (P < 0.001). There was no association between c-kit immunoexpression in malignant melanomas and the clinicopathological criteria, except between the labeling intensity and the degree of intralesional pigmentation (P = 0.048). Our results for labeling extension are in agreement with similar human studies, reinforcing the dog's potential as a model organism for investigation in this type of cancer. In addition, the loss of c-kit expression in malignant melanomas might be a criterion of tumor aggressiveness, indicating that this receptor may be useful in the diagnosis of these tumors.
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PMID:Study of c-kit immunoexpression in canine cutaneous melanocytic tumors. 2240 4

Mast cell-deficient Kit(W-sh) "sash" mice are widely used to investigate mast cell functions. However, mutations of c-Kit also affect additional cells of hematopoietic and nonimmune origin. In this study, we demonstrate that Kit(W-sh) causes aberrant extramedullary myelopoiesis characterized by the expansion of immature lineage-negative cells, common myeloid progenitors, and granulocyte/macrophage progenitors in the spleen. A consistent feature shared by these cell types is the reduced expression of c-Kit. Populations expressing intermediate and high levels of Ly6G, a component of the myeloid differentiation Ag Gr-1, are also highly expanded in the spleen of sash mice. These cells are able to suppress T cell responses in vitro and phenotypically and functionally resemble myeloid-derived suppressor cells (MDSC). MDSC typically accumulate in tumor-bearing hosts and are able to dampen immune responses. Consequently, transfer of MDSC from naive sash mice into line 1 alveolar cell carcinoma tumor-bearing wild-type littermates leads to enhanced tumor progression. However, although it can also be observed in sash mice, accelerated growth of transplanted line 1 alveolar cell carcinoma tumors is a mast cell-independent phenomenon. Thus, the Kit(W-sh) mutation broadly affects key steps in myelopoiesis that may have an impact on mast cell research.
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PMID:Mast cell-deficient Kit(W-sh) "Sash" mutant mice display aberrant myelopoiesis leading to the accumulation of splenocytes that act as myeloid-derived suppressor cells. 2363 54


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