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)

In this review we focus on a promising novel histone deacetylase (HDAC) inhibitor (HA-But) obtained by the esterification of butyric acid (BA), the smallest HDAC inhibitor, with hyaluronic acid (HA), the main constituent of the extracellular matrix which selectively recognizes a transmembrane receptor (CD44) overexpressed in most primary cancers and associated with tumor progression. In vitro, HA-But has proved to be 10-fold more effective than BA in inhibiting the proliferation of a panel of human cancer cell lines, representative of the most common human cancers, and, similar to BA, to regulate the expression of some cell cycle-related proteins, to induce growth arrest in the G1/G0 phase of the cell cycle and to increase histone acetylation. In vivo, HA-But treatment has demonstrated a marked potency in inhibiting primary tumor growth and lung metastases formation from murine Lewis lung carcinoma (LL3) as well as liver metastases formation from intrasplenic implantation of LL3 or B16-F10 murine melanoma cells. In particular, the effect of s.c. and i.p. treatment with HA-But on liver metastases resulted, respectively, in 87 and 100% metastases-free animals, and in a significant prolongation of the survival time compared to the control groups. The results suggest that the presence of the HA backbone does not interfere with the biological activity of butyric residues and that HA-But could represent a promising cell-targetable antineoplastic agent for the treatment of primary and metastatic tumors.
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PMID:Hyaluronic acid butyric esters in cancer therapy. 1574 73

Secreted factors and cell surface receptors can be internalized by endocytosis and translocated to the cytoplasm. Instead of being recycled or proteolysed, they sometimes translocate to the nucleus. Nuclear import generally involves a nuclear localization signal contained either in the secreted factor or its transmembrane receptor, that is recognized by the importins machinery. In the nucleus, these molecules regulate transcription of specific target genes by direct binding to transcription factors or general coregulators. In addition to the transcription regulation, nuclear secreted proteins and receptors seem to be involved in other important processes for cell life and cellular integrity such as DNA replication, DNA repair and RNA metabolism. Nuclear secreted proteins and transmembrane receptors now appear to induce new signaling pathways to regulate cell proliferation and differentiation. Their nuclear localization is often transient, appearing only during certain phases of the cell cycle. Nuclear secreted and transmembrane molecules regulate the proliferation and differentiation of a large panel of cell types during embryogenesis and adulthood and are also potentially involved in wound healing. Secreted factors such as CCN proteins, EGF, FGFs and their receptors are often detected in the nucleus of cancer cells. Nuclear localization of these molecules has been correlated with tumor progression and poor prognosis for patient survival. Nuclear growth factors and receptors may be responsible for resistance to radiotherapy.
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PMID:Nuclear trafficking of secreted factors and cell-surface receptors: new pathways to regulate cell proliferation and differentiation, and involvement in cancers. 1704 74

The interaction between the transmembrane receptor CD44 on epithelial tumor cells and its ligand hyaluronan in the surrounding extracellular matrix is important in tumor progression and metastasis. CD44 is encoded by a single 20-exon gene and expressed in standard form (CD44s), as well as a myriad of CD44 variants (CD44v) generated by alternative splicing of the CD44 mRNA. Previously, we demonstrated that hyaluronan (HA) production is increased at tumor-stroma interface in invasive and metastatic human breast cancers when compared with benign or premalignant lesions. We hypothesize that CD44 expression on breast cancer cells is a major contributing factor to cell adhesion, migration and invasion. To evaluate this hypothesis we examined the effects of 3 distinct anti-CD44s and 2 anti-CD44v6 monoclonal antibodies on breast cancer cell lines that expressed high and low CD44s and CD44v6. Using these antibodies we assessed the role of CD44 in cell adhesion, cell motility, and cell invasion using immobilized HA-coated wells, wound healing assays, and modified Boyden chamber respectively. Our results showed that anti-CD44s could inhibit breast cancer cell adhesion, motility and invasion, while anti-CD44v6 inhibits cell motility. In conclusion, our data suggests that CD44s is involved in breast cancer cell adhesion, motility and invasion through interaction with HA but CD44v6 is involved only in cell motility. Furthermore we concluded that antibodies against different epitopes on CD44 mediate distinct functional effects on breast cancer cells.
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PMID:Role of CD44s and CD44v6 on human breast cancer cell adhesion, migration, and invasion. 1916 78

Tumorigenesis requires the concerted action of multiple pathways, including pathways that stimulate proliferation and metabolism. Epidermal growth factor receptor (EGFR) is a transmembrane receptor-tyrosine kinase that is associated with cancer progression, and the EGFR inhibitors erlotinib/tarceva and tyrphostin/AG-1478 are potent anti-cancer therapeutics. Pgrmc1 (progesterone receptor membrane component 1) is a cytochrome b(5)-related protein that is up-regulated in tumors and promotes cancer growth. Pgrmc1 and its homologues have been implicated in cell signaling, and we show here that Pgrmc1 increases susceptibility to AG-1478 and erlotinib, increases plasma membrane EGFR levels, and co-precipitates with EGFR. Pgrmc1 co-localizes with EGFR in cytoplasmic vesicles and co-fractionates with EGFR in high density microsomes. The findings have therapeutic potential because a Pgrmc1 small molecule ligand, which inhibits growth in a variety of cancer cell types, de-stabilized EGFR in multiple tumor cell lines. EGFR is one of the most potent receptor-tyrosine kinases driving tumorigenesis, and our data support a role for Pgrmc1 in promoting several cancer phenotypes at least in part by binding EGFR and stabilizing plasma membrane pools of the receptor.
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PMID:Pgrmc1 (progesterone receptor membrane component 1) associates with epidermal growth factor receptor and regulates erlotinib sensitivity. 2053

HER-2 and HER-3 are transmembrane receptor proteins that are considered to be important but poorly understood biomarkers in canine tumors. In this study, the expression and the localization of HER-2 and HER-3 were evaluated immunohistochemically in canine mammary tumors (n=64; 12 benign, 52 malignant). HER-2 overexpression was identified in 2/12 (16.7%) benign and in 18/51 (35.3%) malignant cases. HER-3 was expressed in a non-nuclear localization in 11/12 (91.7%) benign and 18/52 (34.6%) malignant tumors. In contrast, HER-3 was expressed in the nucleus of neoplastic cells in 0/12 (0%) benign and 22/52 (42.3%) malignant tumors. Nuclear HER-3 expression was higher in neoplastic epithelial cells compared to myoepithelial cells, and positively correlated with high histological grade and lymphatic vessel invasion. These results suggest that nuclear HER-3 expression is significantly associated with tumor progression and metastasis and may serve as a useful prognostic biomarker in canine malignant mammary tumors.
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PMID:Expression of HER-2 and nuclear localization of HER-3 protein in canine mammary tumors: histopathological and immunohistochemical study. 2127 42

The multifunctional scavenger receptor stabilin-1 (STAB1, FEEL-1, CLEVER-1, KIAA0246) is expressed on tissue macrophages and sinusoidal endothelial cells in healthy organisms, and its expression on both macrophages and different subtypes of endothelial cells is induced during chronic inflammation and tumor progression. Stabilin-1 is a type-1 transmembrane receptor that mediates endocytic and phagocytic clearance of "unwanted-self" components, intracellular sorting of the endogenously synthesized chitinase-like protein SI-CLP, and transcytosis of the growth hormone family member placental lactogen. The central sorting station for stabilin-1 trafficking seems to be the trans-Golgi network (TGN). Transport of stabilin-1 in the TGN requires interaction with GGA adaptors that bind to the classical DDSLL motif and a novel acidic cluster in its cytoplasmic tail. Degradation of stabilin-1 seems to depend on the interaction with sorting nexin 17. However, the mechanisms keeping stabilin-1 on the cell surface remain to be identified. This issue deserves specific attention due to the growing amount of data indicating that function of stabilin-1 in cell adhesion events is essential for inflammation and metastasis. Taking into consideration the complexity of stabilin-1-mediated processes, investigation of stabilin-1 functions in the animal models, as well as mathematic modeling of intracellular trafficking and extracellular contact, would enable prediction of stabilin-1 behavior in complex biological systems and would open perspectives for therapeutic targeting of stabilin-1 pathways in chronic inflammation and carcinogenesis.
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PMID:Multifunctional receptor stabilin-1 in homeostasis and disease. 2095 54

Fibroblast growth factor-inducible 14 (Fn14), a transmembrane receptor binding to the multifunctional cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK), is known to modulate many cellular activities including cancer progression. Here, we demonstrated the significant role of Fn14 in invasion, migration and proliferation of androgen-independent prostate cancer (AIPC) cells. Fn14 and its ligand TWEAK were highly expressed in two AIPC cell lines, DU 145 and PC-3, whereas expression was weak in androgen-sensitive LNCaP cells. Fn14 knockdown using small-interfering RNAs attenuated migration, invasion and proliferation and enhanced apoptosis in the AIPC cell lines. Both forced overexpression of Fn14 by stable Fn14 complementary DNA transfection to PC-3 cells (PC-3/Fn14) and ligand activation by recombinant TWEAK in PC-3 cells enhanced invasion. Fn14 was shown to modulate expression of matrix metalloproteinase (MMP)-9, and MMP-9 mediated the invasive potential influenced by Fn14 in PC-3 cells. In vivo, subcutaneous xenografts of PC-3/Fn14 grew significantly faster than xenograft of PC-3/Mock, and the invasive capacity in PC-3/Fn14 was found to be higher than that of PC-3/Mock as evaluated in an invasion model of the diaphragm. Furthermore, the messenger RNA expressions of MMP-9 in PC-3/Fn14 xenografts were significantly higher than those in PC-3/Mock xenografts. Clinically, high expression of Fn14 was significantly associated with higher prostate-specific antigen recurrence rate in patients who underwent radical prostatectomy. In conclusion, the overexpression of Fn14 may contribute to multiple malignant cellular phenotypes associated with prostate cancer (PCa) progression, in part via MMP-9. TWEAK-Fn14 signaling may be a novel therapeutic target of PCa.
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PMID:Overexpression of Fn14 promotes androgen-independent prostate cancer progression through MMP-9 and correlates with poor treatment outcome. 2182 59

It is now widely recognized that a strong correlation exists between cancer and aberrant hemostasis. Patients with various types of cancers, including pancreatic, colorectal, and gastric cancer, often develop thrombosis, a phenomenon commonly referred to as Trousseau syndrome. Reciprocally, components from the coagulation cascade also influence cancer progression. The primary initiator of coagulation, the transmembrane receptor tissue factor (TF), has gained considerable attention as a determinant of tumor progression. On complex formation with its ligand, coagulation factor VIIa, TF influences protease-activated receptor-dependent tumor cell behavior, and regulates integrin function, which facilitate tumor angiogenesis both in vitro and in mouse models. Furthermore, evidence exists that an alternatively spliced isoform of TF also affects tumor growth and tumor angiogenesis. In patient material, TF expression and TF cytoplasmic domain phosphorylation correlate with disease outcome in many, but not in all, cancer subtypes, suggesting that TF-dependent signal transduction events are a potential target for therapeutic intervention in selected types of cancer. In this review, we summarize our current understanding of the role of TF in tumor growth and metastasis, and speculate on anticancer therapy by targeting TF.
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PMID:The relationship between tissue factor and cancer progression: insights from bench and bedside. 2206 95

The Slit family of secreted proteins and their transmembrane receptor, Robo, were originally identified in the nervous system where they function as axon guidance cues and branching factors during development. Since their discovery, a great number of additional roles have been attributed to Slit/Robo signaling, including regulating the critical processes of cell proliferation and cell motility in a variety of cell and tissue types. These processes are often deregulated during cancer progression, allowing tumor cells to bypass safeguarding mechanisms in the cell and the environment in order to grow and escape to new tissues. In the past decade, it has been shown that the expression of Slit and Robo is altered in a wide variety of cancer types, identifying them as potential therapeutic targets. Further, studies have demonstrated dual roles for Slits and Robos in cancer, acting as both oncogenes and tumor suppressors. This bifunctionality is also observed in their roles as axon guidance cues in the developing nervous system, where they both attract and repel neuronal migration. The fact that this signaling axis can have opposite functions depending on the cellular circumstance make its actions challenging to define. Here, we summarize our current understanding of the dual roles that Slit/Robo signaling play in development, epithelial tumor progression, and tumor angiogenesis.
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PMID:A roundabout way to cancer. 2258 58

CD44 or hyaluronan receptor is a transmembrane receptor associated with aggressive tumour growth, proliferation, and metastasis. In normal physiology, this receptor has a crucial role in cell adhesion, inflammation, and repair processes. However, many tumour cells over-express this receptor and abuse it to become progressive and perpetual units. The article comments from common functioning of the CD44 receptor, to its diabolic multi-dimensional effects in promotion of malignant cells. It also illuminates the relations of CD44 endorsed processes with other biomolecular events in cancer progression. In an end, the review focuses comprehensively at ongoing researches to exploit the CD44 over-expression as a probable target in treatment, management, and diagnosis of malignancy.
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PMID:Role of CD44 in tumour progression and strategies for targeting. 2275 94


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