Comparison of molecular determinants of angiogenesis and lymphangiogenesis in lymph node metastases and in primary tumours of patients with breast cancer

Eynden, G. Van den; Auwera, Ilse Van der; Laere, S. Van; Trinh, X.; Colpaert, C; Dam, Peter van; Dirix, L.; Vermeulen, PB; Marck, E. Van

doi:10.1002/path.2211

Cited by 29 publications

(23 citation statements)

References 49 publications

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“…14,33,34 Decreased PROX1 expression has been found in several cancers, including hepatocellular carcinoma, biliary duct cancer, and breast cancer. [35][36][37] However, in colon cancer, overexpression of PROX1 induces colon cancer progression by promoting a transition from a benign to a highly dysplastic phenotype. 38 In cervical cancer, PROX1 lies within a region of amplification (chromosome 1q) which could suggest that PROX1 copy number gain may function similarly to that in colon cancer.…”

Section: Discussionmentioning

confidence: 99%

Fluorescence in Situ Hybridization Markers for Prediction of Cervical Lymph Node Metastases

Wangsa

Heselmeyer‐Haddad

Ried

et al. 2009

The American Journal of Pathology

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The presence of lymph node metastases is associated with poor prognosis in early stage cervical cancer. As of yet, no molecular markers predicting lymph node metastases have been identified. We examined single genetic markers and a composite marker, comprised of three fluorescence in situ hybridization (FISH) probes targeting the genes LAMP3, PROX1, and PRKAA1, in pretreatment cervical biopsies from 16 lymph node positive cases and 15 lymph node negative controls from women with stage IB and IIA cervical cancer. In addition, we determined clonal patterns by including CCND1 to compare the clonal constitution of primary tumors and associated lymph node metastases. The composite FISH marker allowed for classification of patients into those with and without lymph node metastases with a sensitivity and specificity of 75% and 87%, respectively (P ‫؍‬ 0.001). The positive predictive value and negative predictive value were 86% and 76% , respectively. Clonal patterns varied among the tumors. In many cases , changes between the primary tumor and lymph node metastases in the most common clones may indicate that certain clones have a growth advantage for establishing metastases in lymph nodes. We conclude that the composite FISH marker may be useful for determining risk for subsequent development of lymph node metastases in patients with cervical cancer.

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Section: Discussionmentioning

confidence: 99%

Fluorescence in Situ Hybridization Markers for Prediction of Cervical Lymph Node Metastases

Wangsa

Heselmeyer‐Haddad

Ried

et al. 2009

The American Journal of Pathology

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“…In breast cancer, MMP-2 and VEGF-A are differentially expressed in liver and lymph node (LN) metastasis. 6,7 Similarly, LAMC-2 expression was associated with hematogenous metastasis in bladder cancer. 8 Therefore, we examined whether the type of metastasis (lymphatic vs. hematogenous) and molecular markers were associated with survival in patients with disseminated cervical cancer.…”

Section: Introductionmentioning

confidence: 96%

The type of metastasis is a prognostic factor in disseminated cervical cancer

et al. 2010

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Objective: The objectives of this study were twofold: to verify whether the type of metastasis (lymphatic vs. hematogenous) is a prognostic factor, and to identify molecular markers associated with survival in patients with disseminated cervical cancer. Methods: Between April 1997 and May 2008, 30 patients with disseminated cervical cancer who had supraclavicular lymph node (N=13) or hematogenous metastases (N=17) were initially treated at our institute. We reviewed medical records to extract clinicopathologic variables. For 17 patients with available pathological specimens, we evaluated the association of immunohistochemical staining for metalloproteinase (MMP)-2, vascular endothelial growth factor (VEGF)-A, and laminin V gamma (LAMC)-2 with survival and clinicopathologic variables via a log-rank test and Cox regression analysis. Results: Patients who had only lymphatic metastasis (odds ratio [OR], 5.3; 95% confidence interval [CI], 1.4 to 19.5) or completed initial treatment (OR, 3.2; 95% CI, 1.1 to 9.9) showed better survival than patients who did not, but none of the molecular markers were associated with survival. Out of 13 patients with only lymphatic metastasis, three patients who had received volume-directed radiation with concurrent chemotherapy had a long-term survival of over two years. However, patients with hematogenous metastasis showed extremely poor prognosis. Conclusion:The type of metastasis and completion of initial treatment were associated with prolonged survival in patients with disseminated cervical cancer, and over 20% of patients with lymphatic metastasis were salvaged with volume-directed radiation with concurrent chemotherapy. None of the molecular markers were associated with survival in patients with disseminated cervical cancer.

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“…Recently, it has emerged that modulation of lymphatics and blood vesselsincluding high endothelial venules (HEV), vessels specialized for leukocyte trafficking (7,8)-also occurs in draining LNs of some tumors (9,10). Such alterations can precede the arrival of metastatic cells (7,(11)(12)(13), and members of the VEGF family have been implicated in these changes (12)(13)(14)(15). The importance of alterations to LN endothelium is highlighted by studies of human breast cancer: lymphangiogenesis or angiogenesis within metastatic tumor deposits in sentinel LNs was found to be associated with, and sometimes independently predictive of, distant metastasis or survival (9,16,17).…”

Section: Introductionmentioning

confidence: 99%

A Role for Bone Morphogenetic Protein-4 in Lymph Node Vascular Remodeling and Primary Tumor Growth

et al. 2011

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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. Cancer Res; 71(20); 6547-57. Ó2011 AACR.

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Comparison of molecular determinants of angiogenesis and lymphangiogenesis in lymph node metastases and in primary tumours of patients with breast cancer

Cited by 29 publications

References 49 publications

Fluorescence in Situ Hybridization Markers for Prediction of Cervical Lymph Node Metastases

Fluorescence in Situ Hybridization Markers for Prediction of Cervical Lymph Node Metastases

The type of metastasis is a prognostic factor in disseminated cervical cancer

A Role for Bone Morphogenetic Protein-4 in Lymph Node Vascular Remodeling and Primary Tumor Growth

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