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)

Hyaluronate (HA) is an abundant component of extracellular matrix that is believed to be crucial in many cellular processes, including tissue remodeling, the creation of cell-free spaces, inflammation and tumorigenesis. Although several well characterized proteins within the extracellular matrix associate with HA, it is now clear that cells can also bind and respond to HA directly, via cell-surface HA-binding proteins. The cDNAs coding for two families of such proteins, CD44 and RHAMM, have been cloned and characterized. These proteins have been implicated in a number of physiological processes, including cell migration, lymphocyte activation and tumor progression. Although many of these processes depend on an association with HA, some are apparently HA-independent, suggesting that other ligands for these receptors may be involved.
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PMID:Hyaluronate receptors: key players in growth, differentiation, migration and tumor progression. 753 Apr 64

Polypeptide growth factors are a diverse group of biological regulators. Because they are fundamentally involved in the cellular processes that are important for transformation and progression to malignancy, alterations in growth factor control and in their signal pathways are often observed in tumor cells. In this review, we consider the participation of growth factors and the mechanisms by which they effect tumor progression, using as examples members of the transforming growth factor beta (TGF-beta) and fibroblast growth factor (FGF) families. We explore the hypothesis that although abrogation of TGF-beta negative growth regulation is necessary for transformation, in the later stages of tumor progression, TGF-beta plays a direct role in the enhancement of invasion and metastasis as an autocrine stimulator of these processes. In addition, we present evidence that demonstrates both the potential and the importance of members of the FGF family in transformation and induction of metastasis. Several models of growth factor regulation of malignancy are presented in which we demonstrate (1) a link between TGF-beta 1 mitogenic stimulation of malignant cells and alterations in the expression of ribonucleotide reductase, a key rate-limiting step in the synthesis of DNA and in cell proliferation; (2) autocrine and/or intracrine FGF mitogenic stimulation of malignant cell proliferation and metastasis; and (3) autocrine TGF-beta regulation of malignant cell locomotion and invasion through elevated proteolytic activity and increased synthesis of hyaluronan and RHAMM, a novel hyaluronan cell surface receptor.
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PMID:Transforming growth factor beta and fibroblast growth factor as promoters of tumor progression to malignancy. 824 21

Extracellular matrix molecules and their receptors are important regulators of cell movement, adhesion and cytoskeletal organization. Adhesion molecules can also serve to mediate signal transduction and can influence, and sometimes direct, the events required for tumorigenesis. The extracellular matrix molecule, hyaluronan and its receptors have been implicated in transformation and metastasis, in particular the processes of tumor cell motility and invasion. RHAMM (receptor for hyaluronan mediated motility) is required for the cell locomotion of ras-transformed fibrosarcoma cells, cytokine stimulated fibrobasts and T lymphocytes, malignant B cells, and breast carcinoma cells. HA:RHAMM interactions promote cell locomotion via a protein tyrosine kinase signal transduction pathway that targets focal adhesions. The tyrosine kinase pp60c-src is associated with RHAMM in cells and is required for RHAMM mediated cell motility. It is possible that a RHAMM/src pathway induces focal adhesions to signal the cytoskeletal changes required for elevated cell motility seen in tumor progression, invasion and metastasis.
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PMID:Hyaluronan: RHAMM mediated cell locomotion and signaling in tumorigenesis. 875 Jan 88

RHAMM is an oncogene that regulates signaling through ras and controls mitogen-activated protein kinase [extracellular signal-regulated protein kinase (ERK)] expression in embryonic murine fibroblasts. ERK is a dual-specificity kinase that controls expression of proteins relevant to tumorigenesis, proliferation, and motility. To assess whether RHAMM and ERK are involved in human breast tumor progression, we examined RHAMM, ras, and ERK expression in two cohorts of breast cancer patients using reverse transcription-PCR and immunocytochemistry. We show that overexpression of RHAMM in primary tumors of two patient cohorts was significantly prognostic of poor outcome in breast cancer progression. Furthermore, RHAMM overexpression occurred within subsets of tumor cells in the primary tumor, and this staining pattern was associated with lymph node metastases. The metastases exhibited a significantly higher level of staining for RHAMM than did the primary tumor. RHAMM expression strongly correlated with overexpression of both ras and ERK, although overexpression of either of these two signaling molecules was not by itself a prognostic indicator. These results identify a new parameter that is involved in lymph node metastasis of primary breast cancers and suggest that quantification of RHAMM overexpression may be a useful prognostic indicator for breast carcinoma progression.
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PMID:The overexpression of RHAMM, a hyaluronan-binding protein that regulates ras signaling, correlates with overexpression of mitogen-activated protein kinase and is a significant parameter in breast cancer progression. 953 23

Receptor for hyaluronan (HA)-mediated motility (RHAMM) is a receptor for HA-mediated motility and its expression is correlated with malignancy of ras-transformed cells in that binding of HA to this receptor activates their migratory ability. CD44, a cell surface receptor for HA is also implicated in metastatic behavior of some cancer cells. In this study we examined the relationships of cancer progression with mRNA levels of RHAMM, CD44 (all forms), and exon 6 of CD44 using the real-time reverse transcriptase-polymerase chain reaction method in specimens of colon cancers at different diagnostic stages from 30 patients. Increased mRNA levels of RHAMM were observed in 29 specimens (97%), CD44s (all forms) in 21 specimens (70%), and its exon 6 in 19 specimens (63%) in comparison with those in the corresponding noncancerous tissue specimens. A statistically significant correlation between RHAMM expression and cancerous specimens at any of Dukes' stages A, B, and C was found, and the overexpression of CD44 mRNAs was confirmed in specimens at Dukes' stage C. Thus, our present study for the first time suggests that RHAMM expression may be a clinically useful indicator of colon cancer.
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PMID:Receptor for hyaluronan-mediated motility and CD44 expressions in colon cancer assessed by quantitative analysis using real-time reverse transcriptase-polymerase chain reaction. 1055 29

Interactions of hyaluronic acid (HA) with its binding proteins CD44 and RHAMM (receptor for HA-mediating motility) have been proposed to be important in promoting tumor progression and dissemination. However, a comparative study of their expression patterns in stomach cancer and its associated lesions is not yet available. To address this issue, the combined examinations of pathology, immunocytochemistry and Western blot hybridization were performed on advanced gastric cancer specimens as well as their preneoplastic and non-cancerous counterparts. Alternative CD44 expression was observed in the gastric mucosa with different lesions. CD44 proteins harboring variant exon 6 (CD44 v6) was detected only in cancer tissues with a total positive rate of 14% (10/74). Intracellular RHAMM molecules in Mr 93000 to 95000 were expressed in 3/31 non-cancerous mucosa. RHAMM detection rates increased along with tumor progression. Irrespective of the differences of gross and morphological pattern, majority (54/74) of cancer cases expressed multiple RHAMM isoforms in Mr 40000-45000, 64000, 70000-73000, 85000 and 93000-95000 with the appearance of cell surface immunocytochemical labeling. Among CD44 variant isoforms, v6 is more relevant with malignant transformation of gastric epithelium. Expression of RHAMM, especially the cell surface variants, is closely correlated with tumor progression (P<0.01). Expression of CD44 and RHAMM may benefit the invasion and metastasis of gastric cancer cells presumably in a reciprocal manner.
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PMID:Expression of hyaluronan receptors CD44 and RHAMM in stomach cancers: relevance with tumor progression. 1102 94

Interactions of the extracellular matrix component hyaluronic acid and its cellular receptors CD44 and RHAMM/IHABP have been linked to tumor progression and metastasis formation. We investigated the expression and hyaluronic-acid-dependent functions of CD44 and RHAMM/IHABP in human melanoma. Immunohistochemistry of tumor specimens at different stages of melanoma progression revealed an increased expression of CD44 and RHAMM/IHABP. High mRNA expression of CD44 was found in three highly tumorigenic melanoma cell lines compared with less tumorigenic melanoma cells or nontransformed melanocytes. RHAMM/IHABP expression was upregulated in all cell lines analyzed but not in melanocytes. In contrast to the cell surface localization of CD44, RHAMM/IHABP was detected exclusively within the cytoplasm of melanoma cells. Binding and adhesion of melanoma cells to hyaluronic acid is mainly CD44 dependent as it was inhibited to 60%--80% by an anti-CD44 monoclonal antibody whereas anti-RHAMM/IHABP sera had no effect. Culture of melanoma cells in the presence of hyaluronic acid resulted in a dose-dependent, CD44-mediated increase of melanoma cell proliferation and enhanced release of basic fibroblast growth factor and transforming growth factor beta 1. We conclude that (i) the expression of CD44 and RHAMM/IHABP is increased during melanoma progression, (ii) CD44 is the principal hyaluronic acid surface receptor on melanoma cells, and (iii) the hyaluronic-acid-induced increase of the proliferative capacity of melanoma cells is mainly dependent on CD44--hyaluronic acid interactions.
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PMID:CD44 is the principal mediator of hyaluronic-acid-induced melanoma cell proliferation. 1116 3

The frequent overexpression of the hyaluronan receptors CD44 and RHAMM in cancer cells opens the door for targeting by the naturally-occurring high-M(r) hyaluronan. This is the first time effective in vivo tumor targeting is reported for mitomycin C (MMC) loaded inside nano-sized hyaluronan-liposomes (denoted tHA-LIP). The severe adverse effects of free MMC made it a rational candidate for an effective targeted carrier. In vitro, loading MMC inside tHA-LIP increased drug potency 100-fold, in cells overexpressing, but not in cells underexpressing, hyaluronan receptors. Both types of liposomes were non-toxic and reduced MMC-related toxicity in healthy C57BL/6 mice. In 3 tumor models, BALB/c bearing C-26 solid tumors; C57BL/6 bearing B16F10.9 or (separately) D122 lung metastasis, tHA-LIP were long-circulating, 7-fold and 70-fold longer than nt-LIP and free MMC, respectively. tHA-LIP-mediated MMC accumulation in tumor-bearing lungs was 20% of injected dose, compared to 0.6% and 4% with free drug and nt-LIP, respectively. Tumor-free lungs showed low accumulation, irrespective of drug formulation. Key indicators of therapeutic responses, tumor progression, metastatic burden and survival, were superior (p < 0.001) in animals receiving MMC-loaded tHA-LIP, no treatment, MMC-loaded nt-LIP and free drug. In conclusion, tHA-LIP perform as tumor-targeted carriers, with promising prospects for treatment of tumors overexpressing hyaluronan receptors.
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PMID:Loading mitomycin C inside long circulating hyaluronan targeted nano-liposomes increases its antitumor activity in three mice tumor models. 1469 7

Naturally occurring high-Mr hyaluronan, bound to the surface of nanoliposomes (denoted targeted hyaluronan liposomes, or tHA-LIP), is a candidate for active targeting to tumors, many of which overexpress the hyaluronan receptors CD44 and RHAMM. The surface-bound hyaluronan also provides a hydrophilic coat that, similar to polyethylene glycol, may promote long-term circulation. We recently reported the successful targeting of mitomycin C, mediated by tHA-LIP, in tumor-bearing syngeneic mice. Hypothesizing that this targeting is carrier-specific, rather than drug-specific, we report here studies with doxorubicin (DXR)-loaded tHA-LIP, in syngeneic and human xenograft models. Saline, free DXR, DXR-loaded nontargeted liposomes (nt-LIP), and Doxil served as controls. The tHA-LIP were long-circulating, more than all controls, in healthy and tumor-bearing (C57BL/6/B16F10.9; BALB/c/C-26) mice. Mediated by tHA-LIP, DXR accumulation in tumor-bearing lungs was 30-, 6.7-, and 3.5-fold higher than free DXR, nt-LIP, and Doxil, respectively. Key indicators of therapeutic responses--tumor progression, metastatic burden, and survival--were superior (P < .001) in animals receiving DXR-loaded tHA-LIP compared with controls, in tumor-bearing syngeneic mice (BDF1/P388/ADR ascites, C57BL/6/B16F10.9 lung metastasis, and BALB/c/C-26 solid tumors), and in nude mice bearing PANC-1 solid tumors. In conclusion, tHA-LIP, performing as tumor-targeted carriers, have the potential to join the arsenal of carrier-formulated anticancer drugs.
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PMID:Tumor-targeted hyaluronan nanoliposomes increase the antitumor activity of liposomal Doxorubicin in syngeneic and human xenograft mouse tumor models. 1525 56

RHAMM, a member of the microtubule-associated protein family that interacts with the mitogen-activated protein kinase pathway, is associated with tumor progression, aggressive disease and shortened survival in several tumor types. This study aimed to determine the prognostic value of RHAMM in colorectal cancer (CRC). A series of 1420 unselected, nonconsecutive CRC resections were subdivided into three groups: (1) DNA mismatch repair (MMR)-proficient, (2) MLH1 negative and (3) presumed Lynch syndrome. Immunohistochemical analysis of RHAMM expression (0 vs >0%), increasing expression (increasing percentage positivity) and complete expression (100 vs <100%) was performed using tissue microarray technique and the results were correlated with clinicopathological parameters. Fifty-seven tissue samples of normal colonic mucosa were included as a control group. In a univariate analysis increasing and complete expression of RHAMM were associated with higher N stage (P=0.023 and 0.021) and worse survival (P<0.0001) in MMR-proficient CRC. Complete expression of RHAMM was associated with worse survival in presumed Lynch syndrome (P=0.016). In MLH1-negative CRC there was no association between RHAMM expression and the clinicopathological features. In a multivariate analysis, increasing RHAMM expression was an independent adverse prognostic factor in MMR-proficient CRC (P<0.0001) and complete expression in MMR-proficient CRC and presumed Lynch syndrome (P<0.0001 and P=0.031, respectively). Nuclear pERK expression was associated with increasing RHAMM expression in MMR-proficient CRC (P=0.012) and with complete RHAMM expression in presumed HNPCC (P=0.03). Increasing and complete RHAMM expressions are independent adverse prognostic factors in MMR-proficient CRC and presumed Lynch syndrome.
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PMID:Overexpression of the receptor for hyaluronic acid mediated motility is an independent adverse prognostic factor in colorectal cancer. 1676 11


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