Abstract
BackgroundMalignant melanoma of the skin can metastasize through blood vessels and lymphatics. The primary tumor develops a vascular microenvironment characterized by abnormal blood vessels and lymphatics and a physicochemical microenvironment characterized by low oxygen tension, regions with hypoxic tissue, and high interstitial fluid pressure (IFP). This study aimed at identifying relationships between the metastatic route of melanomas and characteristic features of the microvascular and physicochemical microenvironments of the primary tumor.MethodsTwo patient-derived xenograft (PDX) models (E-13, N-15) and four cell line-derived xenografts (CDX) models (C-10, D-12, R-18, T-22) of human melanoma were included in the study. Tumors were transplanted to an orthotopic site in BALB/c-nu/nu mice, and when the tumors had grown to a volume of 500–600 mm3, the IFP of the primary tumor was measured and the hypoxia marker pimonidazole was administered before the host mouse was euthanized. The primary tumor, lungs, and six pairs of lymph nodes were evaluated by examining hematoxylin/eosin-stained and immunostained histological preparations. The expression of angiogenesis-related genes was assessed by quantitative PCR.ResultsC-10, D-12, and E-13 tumors disseminated primarily by the hematogenous route and developed pulmonary metastases. These tumors showed high angiogenic activity and high expression of the F3 gene as well as ANGPT2 and TIE1, genes encoding proteins of the angiopoietin–tie system. N-15, R-18, and T-22 tumors disseminated mainly by the lymphogenous route and developed metastases in draining lymph nodes. These tumors had highly elevated IFP and showed high expression of NRP2, a gene encoding neuropilin-2.ConclusionThe primary metastatic route of orthotopic human melanoma xenografts and the development of lung and lymph node metastases are influenced significantly by the microvascular and physicochemical microenvironments of the primary tumor.
Highlights
Malignant melanoma of the skin can metastasize through blood vessels and lymphatics
The N-15, R-18, and T-22 models showed higher incidence of lymph node metastasis than the C-10, D-12, and E-13 models (p = 0.016; Fig. 1c), whereas the incidence of pulmonary metastasis was higher in the C-10, D-12, and E-13 models than in the N-15, R-18, and T-22 models (p = 0.0012; Fig. 1d)
Lymph node metastases develop primarily from tumor cells disseminated through lymphatics associated with the primary tumor, whereas the development of pulmonary metastases can be a result of tumor cell dissemination through primary tumor-associated blood vessels as well as tumor cell dissemination from lymph node metastases [6, 14, 16]
Summary
Malignant melanoma of the skin can metastasize through blood vessels and lymphatics. The primary tumor develops a vascular microenvironment characterized by abnormal blood vessels and lymphatics and a physicochemical microenvironment characterized by low oxygen tension, regions with hypoxic tissue, and high interstitial fluid pressure (IFP). Intravital microscopy studies have revealed that the blood vessel networks of melanomas in human patients show severe morphological abnormalities, including vessel disorganization, aberrant vessel bifurcations, heterogeneous vessel density, vessel tortuosity, increased vessel segment lengths, and highly permeable vessel walls [17]. These abnormalities cause irregular and heterogeneous blood flow, and may lead to the development of a physicochemical tumor microenvironment characterized by poor oxygenation and elevated interstitial fluid pressure (IFP) [18, 19]. Clinical investigations have revealed that low oxygen tension, hypoxic tumor regions, and high IFP are characteristic features of the physicochemical microenvironment of human melanomas [20,21,22,23]
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