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Lymphatic metastasis of mammary adenocarcinoma. An experimental study in the rat with a brief review of the literature.

When 5 million cells of the solid form 13762 rat mammary carcinoma are implanted into the footpad of syngeneic rats there is consistent (approximately 100%) metastasis to the draining popliteal node and thence up the lymphatic chain to the lungs. With the transmission electron microscope tumor cells are seen to penetrate gaps in the lymphatic endothelium, probably but not certainly, between endothelial cells. There is neither widespread patency nor significant destruction of lymphatic endothelium. The tumor cells penetrate in groups and lie in the lymphatic in groups with some evidence of acinar differentiation. Tumor cells lodge in groups in the subcapsular sinus and progressively pass down the radial sinusoids and destroy the node; as they grow there is extensive differentiation into adenocarcinoma. The draining lymph obtained by cannulation does not contain an increase in total cells. A few tumor cells are present mostly in clumps. Recruitment is continuous but not progressively increasing. Any theories on neoplastic invasion and metastasis must take into consideration possible aggregation of some tumor cell types in groups. The literature on experimental lymphatic metastasis is reviewed briefly.

Adenocarcinoma↗

[Relationship among expression of vascular endothelial growth factor-C(VEGF-C), angiogenesis, lymphangiogenesis, and lymphatic metastasis in oral cancer].

BACKGROUND & OBJECTIVE: There may be a close relationship among the vascular endothelial growth factor-C (VEGF-C) expression, peritumour lymphatic vessels, and lymph node metastasis. The purpose of this study was to compare the relationship among VEGF-C mRNA expression, density of lymphatic and blood vessels, and lymphatic metastasis in oral squamous carcinoma. METHODS: VEGF-C mRNA was determined by RT-PCR. Lymphatic and blood vessel differential stain was determined by enzyme-histochemical technique. Automated image analysis quantification was applied to determine the number of total lymphatic and blood vessels in unit area (TNa). RESULTS: The peri-tumor lymphatic TNa of oral carcinoma was significantly higher in VEGF-C-positive group than those in VEGF-C-negative group(26.42 +/- 5.85: 17.34 +/- 6.48) (P < 0.01), but the blood TNa was a few higher(35.16 +/- 15.55: 33.49 +/- 13.73) (P > 0.05). Lymphatic TNa (30.67 +/- 5.76: 21.94 +/- 5.84) (P < 0.01) and blood TNa (44.19 +/- 14.29: 30.61 +/- 11.82) (P < 0.01) were significantly higher in lymph node metastasis group than those in no-metastasis group. CONCLUSION: VEGF-C mainly promotes peri-tumor lymphangiogenesis and has a little effect on angiogenesis. Simultaneous increase of lymphatic and blood vessels may be related to the synergic expression of VEGF, VEGF-C and their receptors.

Adult↗

Tumor-induced activation of lymphatic endothelial cells via vascular endothelial growth factor receptor-2 is critical for prostate cancer lymphatic metastasis.

Prostate cancer disseminates initially and primarily to regional lymph nodes. However, the nature of interactions between tumor cells and lymphatic endothelial cells (LEC) is poorly understood. In the current study, we have isolated prostate LECs and developed a series of two-dimensional and three-dimensional in vitro coculture systems and in vivo orthotopic prostate cancer models to investigate the interactions of prostate cancer cells with prostate LECs. In vitro, highly lymph node metastatic prostate cancer cell lines (PC-3 and LNCaP) and their conditioned medium enhanced prostate LEC tube formation and migration, whereas poorly lymph node metastatic prostate cancer cells (DU145) or normal prostate epithelial cells (RWPE-1) or their conditioned medium had no effect. In vivo, the occurrence of lymphatic invasion and lymph node metastasis was observed in PC-3 and LNCaP xenografts but not in DU145 xenografts. Furthermore, vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 is expressed by prostate LECs, and its ligands VEGF-A, VEGF-C, and VEGF-D are up-regulated in highly lymph node metastatic prostate cancer cells. Recombinant VEGF-A and VEGF-C, but not VEGF-C156S, potently promoted prostate LEC tube formation, migration, and proliferation in vitro, indicating that signaling via VEGFR-2 rather than VEGFR-3 is involved in these responses. Consistent with this, blockade of VEGFR-2 significantly reduced tumor-induced activation of LECs. These results show that the interaction of prostate tumor cells with LECs via VEGFR-2 modulates LEC behavior and is related to the ability of tumor cells to form lymph node metastases.

Adenocarcinoma↗

Mode of spread in the early phase of lymphatic metastasis in non-small-cell lung cancer: significance of nodal micrometastasis.

The impact of lymphatic micrometastases on prognosis of non-small-cell lung cancer has not been clearly established. We therefore prospectively assessed the frequency, mode of mediastinal spread, and prognostic significance of lymphatic micrometastases in lymph nodes of 93 patients with completely resected non-small-cell lung cancer staged as pT1 to pT4 pN0 and pN1 by conventional histopathologic techniques. Frozen tissue sections from 471 lymph nodes that were staged as free of metastases by routine histopathologic examination were screened for micrometastases by the alkaline phosphatase-antialkaline phosphatase immunostaining technique with the monoclonal antibody Ber-Ep-4. Twenty of 73 patients (27.4%) with disease staged as pN0 and nine of 20 patients (45.0%) with disease staged as pN1 had nodal micrometastases. Eight of 17 patients with upper lobe primary tumors and five of 12 patients with lower lobe primary tumors exhibited skip micrometastases. Mean relapse-free survival was significantly increased in patients with pN0 disease without micrometastases (41.1 vs 29 months, p = 0.0081). In patients with pN1 disease, mean relapse-free and cancer-related survivals were also significantly increased if no micrometastases were found (34.8 and 38.2 months vs 18 and 23.5 months, p = 0.0157 and p = 0.0094). Patients with disease staged as pN0 and pN1 with micrometastases revealed no difference in cancer-related survival compared with a control population of patients with disease staged as pN2. The mode of spread was erratic. The prognosis of patients after upstaging of pN0 and pN1 disease according to results of immunohistochemical staining correlated strongly with the prognosis of patients whose disease was staged at the higher stages by conventional histopathologic examination. These findings could represent a new indication for adjuvant therapy, supporting extensive lymph node sampling for staging purposes.

Adult↗

Expression of Vicia villosa agglutinin (VVA)-binding glycoprotein in primary breast cancer cells in relation to lymphatic metastasis: is atypical MUC1 bearing Tn antigen a receptor of VVA?

Aberrant carbohydrate expression frequently occurs in breast cancer and may endow cells with metastatic potential. Here we first studied the relationship between expression of Vicia villosa agglutinin (lectin) (VVA)-binding carbohydrates and aggressive breast cancer. We then investigated the molecular characteristics of these glycoproteins and compared them with those of glycoproteins recognized by the mouse anti-Tn monoclonal antibody (MAb) HB-Tn1. Histochemical studies of samples from 322 cases of invasive ductal carcinoma demonstrated that VVA-binding carbohydrate expression correlated with tumor stage, lymphatic invasion, and lymph node metastasis (p=0.0385, p=0.0019, and p=0.0430. respectively). Western blotting analysis of frozen materials from 39 cases, under denaturing and reducing conditions, revealed that the major cancer cell-specific VVA-binding proteins were molecules of about 30, 33, and >200 kDa. Cases expressing the approximately 33 kDa molecule had significant lymphatic invasion more frequently than did cases not expressing this molecule (p=0.0076). Binding of VVA to the approximately 30 and approximately 33 kDa molecules was completely lost by preincubation of VVA with 1 mM Tn antigen (N-acetylgalactosamine alpha1-O-serine). The VVA-binding molecules appeared to react with VU-3C6 anti-MUC1 MAb. Expression of HB-Tn1 in breast cancer cells showed significant correlation with expression of VVA-binding carbohydrate(s) (p<0.0001) but HB-Tn1 reactivity was not clearly related to breast cancer aggressiveness. Because anti-Tn MAbs bound to Tn antigen clusters, we concluded that atypical MUC1 bearing the noncluster form of Tn antigen is implicated in aggressive growth of primary breast cancer cells, particularly in lymphatic metastasis.

Adult↗

Cell biology of lymphatic metastasis. The potential role of c-erbB oncogene signalling.

Lymphatic metastases are an important indicator of the malignancy of epithelial cancers. Empirical clinical observations associating specific genetic abnormalities with tumour progression, allied with basic laboratory investigations, are providing not only improved prognostic and diagnostic opportunities, but also a detailed understanding of the molecular machinery of metastasis. One such association--between the c-erbB oncogene family and metastasis--has proved particularly instructive. Functional links between over-expression (and occasionally mutational activation) of c-erbB-1 (EGFR) and c-erbB-2 and specific phenotypes of metastatic cells have been elucidated. Activated c-erbB oncogenes potentiate tumour cell adhesion to endothelial cells and upregulate VEGF, potentially facilitating angiogenesis and vascular invasion. In addition, cells over-expressing these oncogenes frequently show aberrant cell-cell and cell-matrix interactions, mediated by changes in integrin and cadherin function. Thirdly, both EGFR and c-erbB-2 signalling can significantly upregulate specific matrix metalloproteinases, key enzymes involved in angiogenesis and invasion. Finally, c-erbB receptors linked to the actin cytoskeleton and highly expressed on invadopodia, are thought to assist cell migration. Taken together, these observations suggest that such receptors can act as "master switches" in metastasis, whose activation co-ordinately controls events normally utilised in development, now subverted by the metastatic cell. As such, they represent ideal targets for therapeutic intervention.

Cell Adhesion↗