Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Advances in surgical treatment, including sentinel lymphadenectomy, permit the pathologic staging of regional lymph nodes most likely to contain metastasis by identifying afferent lymphatic channels, which specifically drain the primary tumor site. Recently, a new member of the angiogenic molecule in VEGF family, VEGF-D, has been identified that induces lymphangiogenesis via high-affinity binding to VEGFR-3. VEGF-D is predominantly expressed in lymphatic endothelium. We have previously developed a novel method for the isolation of anatomically-defined lymphatic endothelial cells (LECs) from human sentinel lymphatic channel during SLN biopsy. The effect of VEGF-D on the extracellular signal-regulated kinases (Erk)-1/2 and Akt signaling pathway was examined by Western blot analysis. VEGF-D (500 ng/ml) apparently upregulated phospho-p44/phospho-p42 activity in human isolated LECs by Western blot analysis, while phospho-Akt activity was not at all changed by VEGF-D exposure without the change of total p44/p42 and Akt expression. U0126 (20 microM), the MEK1/2 inhibitor, could completely block the VEGF-D induced phospholylation of Erk1/2 signaling pathway. These data demonstrate that VEGF-D induces p44/p42 in human LECs and suggests that this signaling pathway activation may be important in LEC biology and lymphoangiogenesis, which may lead to the progression of new strategies of cancer treatment.
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PMID:[Effects of vascular endothelial growth factor D on the signaling cascade of sentinel lymphatic endothelial cells from melanoma patients undergoing sentinel lymphadenectomy]. 1521 74

Nearly four centuries after the discovery of lymphatic vessels, the molecular mechanisms underlying their development are beginning to be elucidated. Vascular endothelial growth factor C (VEGF-C) and VEGF-D, via signaling through VEGFR-3, appear to be essential for lymphatic vessel growth. Observations from clinicopathological studies have suggested that lymphatic vessels serve as the primary route for the metastatic spread of tumor cells to regional lymph nodes. Recent studies in animal models have provided convincing evidence that tumor lymphangiogenesis facilitates lymphatic metastasis. However, it is not clear how tumor-associated lymphangiogenesis is regulated, and little is known about how tumor cells escape from the primary tumor and gain entry into the lymphatics. This review examines some of these issues and provides a brief summary of the recent developments in this field of research.
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PMID:Role of lymphangiogenic factors in tumor metastasis. 1498 63

We report the case of a 52-year-old woman with occult breast cancer who presented with a hard metastatic nodule in the left axilla. Although histology identified a metastatic adenocarcinoma in the lymph nodes, numerous tests failed to detect the primary tumor. Immunohistochemistry showed that the resected lymph node was positive for both estrogen and progesterone receptors, suggesting the breast as the site of the primary tumor. Left modified radical mastectomy was performed. Pathology revealed an invasive ductal carcinoma (1.5x1 mm in size) with extensive lymphatic involvement, which strongly expressed both vascular endothelial growth factor-C (VEGF-C) and VEGF-D.
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PMID:Occult breast cancer presenting as axillary metastases. 1599 65

Uveal melanoma develops in one of the most capillary-rich tissues of the body and is disseminated hematogenously. Knowledge of the nature and the spatiotemporal expression of angiogenic factors in uveal melanoma is essential to the development of new treatment strategies, especially with regard to improving survival. In this study, we measured the angiogenic potential of several angiogenic factors in different uveal melanoma cell lines, in an in vivo model, and in primary tumor material from patients with melanoma. Most uveal melanoma cell lines expressed vascular endothelial growth factor (VEGF)-A (isoforms 121, 165, 189), VEGF-B, VEGF-C, VEGF-D, and basic fibroblastic growth factor (b-FGF) to various extents. The expression of VEGF-A 121 was always higher than that of the other VEGF-A isoforms, suggesting that VEGF-A 121 is the most abundant VEGF-A isoform. All experimentally induced tumors expressed VEGF-A, VEGF-B, VEGF-C, VEGF-D, and basic fibroblastic growth factor (b-FGF). Similarly, significant amounts of mRNA for VEGF-B, VEGF-C, VEGF-D, and b-FGF were detected in uveal melanoma material from patients. In contrast, VEGF-A mRNA (121, 165, 189) was low (9/28) or not detectable in the tumor samples. The synthesis of VEGF-A 165 and b-FGF protein by various cell lines was measured by enzyme-linked immunosorbent assay (ELISA). Most uveal melanoma cell lines, but not normal melanocytes, strongly synthesized and secreted VEGF-A 165 and b-FGF during cell culture. Our data suggest that the expression of (lymph) angiogenic factors may play a causal role in the angiogenesis and progression of uveal melanoma and distant metastasis.
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PMID:Angiogenic profile of uveal melanoma. 1696 50

Vascular endothelial growth factor receptor 3 (VEGFR-3) binds VEGF-C and VEGF-D and is essential for the development of the lymphatic vasculature. Experimental tumors that overexpress VEGFR-3 ligands induce lymphatic vessel sprouting and enlargement and show enhanced metastasis to regional lymph nodes and beyond, whereas a soluble form of VEGFR-3 that blocks receptor signaling inhibits these changes and metastasis. Because VEGFR-3 is also essential for the early blood vessel development in embryos and is up-regulated in tumor angiogenesis, we wanted to determine if an antibody targeting the receptor that interferes with VEGFR-3 ligand binding can inhibit primary tumor growth. Our results show that antibody interference with VEGFR-3 function can inhibit the growth of several human tumor xenografts in immunocompromised mice. Immunohistochemical analysis showed that the blood vessel density of anti-VEGFR-3-treated tumors was significantly decreased and hypoxic and necrotic tumor tissue was increased when compared with tumors treated with control antibody, indicating that blocking of the VEGFR-3 pathway inhibits angiogenesis in these tumors. As expected, the anti-VEGFR-3-treated tumors also lacked lymphatic vessels. These results suggest that the VEGFR-3 pathway contributes to tumor angiogenesis and that effective inhibition of tumor progression may require the inhibition of multiple angiogenic targets.
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PMID:Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth. 1723 68

The metastatic spread of tumor cells is the most lethal aspect of cancer and often occurs via the lymphatic vasculature. Both experimental tumor models and human clinicopathologic data indicate that growth of lymphatic vessels (lymphangiogenesis) near solid tumors is often associated with lymph node metastasis. Changes in the adhesive properties of lymphatic endothelium near tumors may also facilitate metastatic spread via the lymphatics. Lymphangiogenic growth factors have been identified that promote formation of tumor lymphatics and metastatic spread of tumor cells to lymph nodes. These include the secreted glycoproteins vascular endothelial growth factor-C (VEGF-C) and VEGF-D, which act via their cognate receptor tyrosine kinase VEGF receptor-3 (VEGFR-3) located on lymphatic endothelial cells. Other signaling molecules that have been reported to promote lymphangiogenesis and/or lymphatic metastasis in cancer include VEGF-A, platelet-derived growth factor-BB, and hepatocyte growth factor. However, the quantitative contribution of these proteins to tumor lymphangiogenesis and lymphatic metastasis in different tumor types requires further investigation. In addition, chemokines are thought to play a role in attracting tumor cells and lymphatic vessels to each other. Moreover, it has recently been shown that lymphangiogenic growth factors secreted from a primary tumor can induce lymphangiogenesis in nearby lymph nodes, even before arrival of tumor cells, which may facilitate further metastasis. This article provides an overview of the molecular mechanisms that control lymphatic metastasis and discusses potential therapeutic approaches for inhibiting this process in human cancer.
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PMID:Molecular control of lymphatic metastasis. 1851 75

Up to 30% of curatively resected colorectal cancer patients with tumor-negative lymph nodes, show disease recurrence. We assessed whether these high-risk patients can be identified by examining primary tumors for the following blood and lymphatic vasculature markers: A) sialyl Lewis X (sLeX), vascular endothelial growth factor (VEGF)-C and VEGF-D expression; B) blood and lymphatic microvessel density (BMVD/LMVD); and C) the presence of blood and lymphatic vessel invasion. Thirty-six cases (disease recurrence within 5 years) and 72 controls (no disease recurrence for at least 5 years) were selected in a case-control design. Tumor sections were stained by antibodies CSLEX1 (sLeX), anti-VEGF-C, anti-VEGF-D, anti-CD31 (BMVD) or D2-40 (LMVD) to determine the parameters as mentioned above. A multivariate analysis showed sLeX expression and high LMVD (odds ratio 5.1, 95% confidence interval 1.3-20.0 and odds ratio 3.1, 95% confidence interval 1.0-10.0, respectively) to be independent factors predicting disease recurrence. Expression of sLeX correlated with liver metastases (P = 0.015). A high LMVD was related to regional intra-abdominal or intrapelvic metastases in lymph nodes and distant metastases other than in the liver and lungs such as peritoneum, bones, brain and adrenal glands (P = 0.004). A high BMVD in the invasive front correlated with lung metastases (P = 0.018). We show that high-risk node-negative colorectal cancer patients can be identified by primary tumor assessment for sLeX expression and LMVD. Our results are consistent with the notion that both lymphatic and hematogenous metastasis play a role in colorectal cancer.
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PMID:Sialyl Lewis X expression and lymphatic microvessel density in primary tumors of node-negative colorectal cancer patients predict disease recurrence. 1930 92

The main factor that affects the prognosis of patients with oral squamous cell carcinoma (OSCC) is regional lymph node metastases, which usually spreads first to the sentinel lymph nodes (SLNs). Recent studies have demonstrated that tumor cells in several malignancies can induce lymphangiogenesis in SLNs before metastasizing. To elucidate the mechanisms of tumor dissemination of OSCC, we investigated whether primary tumors induce lymphangiogenesis within SLNs in patients with OSCC. The mRNA expression of lymphatic-specific markers, including VEGFR-3, Prox-1, and LYVE-1 in 23 metastasis-negative SLNs obtained from 10 patients with OSCC, was investigated using a quantitative real-time RT-PCR assay, and compared with control lymph nodes from patients with non-cancerous diseases. In addition, VEGF-C and VEGF-D expressions of the primary tumor were examined by immunohistochemistry. In SLNs, there were highly significant correlations between the three lymphatic markers examined. Interestingly, the level of LYVE-1 expression in SLNs, despite the absence of metastasis, was significantly higher than in control lymph nodes. Moreover, SLNs from patients with VEGF-C-positive tumor showed a significantly higher expression of VEGFR-3 than those from patients with VEGF-C-negative tumor. Our findings suggest that in OSCC, the primary tumor actively induces lymphangiogenesis in SLNs prior to the onset of metastases, and where tumor-derived VEGF-C plays an important role.
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PMID:Primary tumor induces sentinel lymph node lymphangiogenesis in oral squamous cell carcinoma. 2030 6

Lymphatic metastasis plays a critical role in ovarian cancer, indicates poor prognoses and correlates to the majority of cancer deaths. Camptothecin derivatives exhibit promising activity for the treatment of solid tumors because of its specific inhibition of eukaryotic DNA topoisomerase I. Yet, its application is hindered due to extreme water insolubility and severe side effects. It is essential to establish an efficient and safe protocol for the administration of camptothecin versus tumor metastasis and growth. In the current research, we encapsulated camptothecin with N-trimethyl chitosan (CPT-TMC) to increase its water-solubility and lower its side effects, and tested it on a high potential lymphogenous metastatic model of human ovarian cancer. In the prophase study, we successfully transfected SKOV3 cells with VEGF-D recombinant plasmid DNA (pcDNA3.1(+)/VEGF-D) to construct a cell line named SKOV3/VEGF-D and establish a feasible lymphogenous metastatic model. The antitumor and antimetastatic activities of CPT-TMC were evaluated in nude mice subcutaneously inoculated with SKOV3/VEGF-D cells at the left hindlimb claw pad. The tumor-bearing mice were divided randomly into four groups and treated twice per week for three weeks. Evan's Blue Dye was used to delineate functional lymphatic vessels. Lymphatic metastasis rates were detected by hematoxylin and eosin (HE) staining. Expression of VEGF-D and MMP-9 were investigated by immunohistochemistry. In contrast to controls, administration of CPT-TMC achieved effective inhibition in primary tumor volume and lymphogenous metastasis, yet without apparent systemic toxic effects. These effects were associated with simultaneously down-regulated VEGF-D and MMP-9 expression, significantly decreased tumor-associated lymphatic and blood sprouts, tremendously reduced systemic toxic effects, dramatically increased tumor apoptotic index. Our data indicate that CPT-TMC is superior to CPT by maximizing its anticancer and antimetastatic activities with minimal toxicity on hosts. CPT-TMC may become a potentially therapeutic strategy against human advanced ovarian cancer.
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PMID:The antitumor and antimetastatic effects of N-trimethyl chitosan-encapsulated camptothecin on ovarian cancer with minimal side effects. 2081 74

Lymph node metastasis, an early and prognostically important event in the progression of many human cancers, is associated with expression of VEGF-D. Changes to lymph node vasculature that occur during malignant progression may create a metastatic niche capable of attracting and supporting tumor cells. In this study, we sought to characterize molecules expressed in lymph node endothelium that could represent therapeutic or prognostic targets. Differential mRNA expression profiling of endothelial cells from lymph nodes that drained metastatic or nonmetastatic primary tumors revealed genes associated with tumor progression, in particular bone morphogenetic protein-4 (BMP-4). Metastasis driven by VEGF-D was associated with reduced BMP-4 expression in high endothelial venules, where BMP-4 loss could remodel the typical high-walled phenotype to thin-walled vessels. VEGF-D expression was sufficient to suppress proliferation of the more typical BMP-4-expressing high endothelial venules in favor of remodeled vessels, and mechanistic studies indicated that VEGF receptor-2 contributed to high endothelial venule proliferation and remodeling. BMP-4 could regulate high endothelial venule phenotype and cellular function, thereby determining morphology and proliferation responses. Notably, therapeutic administration of BMP-4 suppressed primary tumor growth, acting both at the level of tumor cells and tumor stromal cells. Together, our results show that VEGF-D-driven metastasis induces vascular remodeling in lymph nodes. Furthermore, they implicate BMP-4 as a negative regulator of this process, suggesting its potential utility as a prognostic marker or antitumor agent.
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PMID:A role for bone morphogenetic protein-4 in lymph node vascular remodeling and primary tumor growth. 2186 59


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