fibrin and Skin-Neoplasms

The V2 carcinoma, established from skin carcinomas of cottontail rabbits and transplantable in all strains of domestic rabbits, is a paradigm of invasiveness attainable by squamous cell carcinoma. The main mechanisms contributing to this potential are the pressure of incessant cell proliferation, the capacity of the tumor to grow in compact as well as in dissociated formation, the synthesis of proteinases (chiefly cathepsin B and collagenases) by the tumor cells, and the latter's migratory activity. In addition, the V2 carcinoma elicits a large spectrum of host reactions which favor partly the organism, partly the tumor and thus create the complexity of the invasion phenomenon.

Topics: Animals; Carcinoma, Squamous Cell; Cathepsin B; Cathepsins; Cell Division; Cell Movement; Cottontail rabbit papillomavirus; Disease Models, Animal; Epithelium; Extracellular Matrix; Fibrin; Fibroblasts; Hypercalcemia; Leukocytes; Microbial Collagenase; Neoplasm Invasiveness; Neoplasm Transplantation; Neovascularization, Pathologic; Papilloma; Rabbits; Skin Neoplasms; Tumor Virus Infections

During the last 25 years, cutaneous biologists have been particularly interested in abnormal cutaneous vascular patterns, the profusion of capillary anastomoses, the leakiness of venules, clotting, fibrinolysis, and blood viscosity. As a result, the effects of hypoxia and the factors that encourage new vessel proliferation are better understood than before. Only when the biologic behavior of the two extremes of growth from hypoplasia to hyperplasia is studied and compared can the blood supply of a tissue be understood. Hyperplastic tissues are seen in wounds, psoriasis, cancer, and in selected sites of chronic stasis and hypoxia where the vessels are extremely permeable, where blood cells easily escape, and where lymphatics dilate and proliferate. The proliferation of other tissues, such as endothelium, epithelium, mast cells, and probably of locally infective organisms, is also encouraged in hyperplasia. Moreover, fibrinolysis does not occur and fibrin is deposited, the electrostatic charge on the internal vascular surface becomes more positive, and the organ is more vulnerable to subsequent injury. Atrophic or hypoplastic tissues have a reduced cellular turnover and are less hypoxic. The vessels are less permeable, blood cells do not escape, there is only a slight tendency to clot, and fibrinolysis is often increased. Lymphatics are sparse and infection is not a feature. The electrostatic charge on the internal surface of the vessel is negative.

Topics: Animals; Blood Viscosity; Capillaries; Cell Membrane; Disseminated Intravascular Coagulation; Fibrin; Fibrinolysis; Humans; Hypoxia; Ischemia; Skin; Skin Neoplasms; Telangiectasis

An increasing number of studies suggest inflammation stimulates tumour invasion. In melanoma, despite recent advances in targeted therapy and immunomodulatory therapies, this cancer remains difficult to treat. Our previous studies show melanoma cells interact with skin cells in their invasion into tissue engineered skin and suggest inflammation stimulates invasion. The aim of this study was to investigate the use of an anti-inflammatory on melanoma invasion. To do this we developed a wounded and inflamed in vitro 3D melanoma model in which to investigate the use of an anti-inflammatory on melanoma invasion. The tissue engineered skin model was based on human de-epidermised acellular dermis to which keratinocytes, fibroblasts and three different melanoma cell lines were added in various combinations. A simple incisional wound was made in the model and TNF-α and fibrin were added to simulate conditions of inflammation. Topical ibuprofen in a hydrogel was added and the extent of melanoma invasion into the dermis was assessed under the various conditions. The results showed that penetration of two of the cell lines (HBL and A375SM) into the tissue engineered skin was exacerbated by wounding and ibuprofen significantly decreased invasion of A375SM cells and slightly reduced invasion of HBL cells. A third cell line, C8161, was aggressively invasive under all conditions to an extent that was not influenced by wounding, TNF-α or the addition of ibuprofen. In summary, the results for one these cell lines (and a trend for a second cell line) support the hypothesis that a wound environment is conducive to melanoma invasion but the local addition of an anti-inflammatory drug such as ibuprofen may attenuate invasion.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Cell Culture Techniques; Cell Line, Tumor; Cell Movement; Fibrin; Fibroblasts; Humans; Ibuprofen; Keratinocytes; Melanoma; Models, Biological; Neoplasm Invasiveness; Skin Neoplasms; Tissue Engineering; Tumor Necrosis Factor-alpha

Tumour-repopulating cells (TRCs) are a self-renewing, tumorigenic subpopulation of cancer cells critical in cancer progression. However, the underlying mechanisms of how TRCs maintain their self-renewing capability remain elusive. Here we show that relatively undifferentiated melanoma TRCs exhibit plasticity in Cdc42-mediated mechanical stiffening, histone 3 lysine residue 9 (H3K9) methylation, Sox2 expression and self-renewal capability. In contrast to differentiated melanoma cells, TRCs have a low level of H3K9 methylation that is unresponsive to matrix stiffness or applied forces. Silencing H3K9 methyltransferase G9a or SUV39h1 elevates the self-renewal capability of differentiated melanoma cells in a Sox2-dependent manner. Mechanistically, H3K9 methylation at the Sox2 promoter region inhibits Sox2 expression that is essential in maintaining self-renewal and tumorigenicity of TRCs both in vitro and in vivo. Taken together, our data suggest that 3D soft-fibrin-matrix-mediated cell softening, H3K9 demethylation and Sox2 gene expression are essential in regulating TRC self-renewal.

Topics: Animals; Biosensing Techniques; Cell Line, Tumor; Cell Proliferation; Disease Progression; DNA Methylation; Female; Fibrin; Fluorescence Resonance Energy Transfer; Gene Silencing; Histone-Lysine N-Methyltransferase; Histones; Integrin beta1; Lysine; Melanoma; Melanoma, Experimental; Methylation; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasm Transplantation; Neoplastic Stem Cells; Promoter Regions, Genetic; RNA, Small Interfering; Skin Neoplasms; SOXB1 Transcription Factors; Time Factors

Rearrangement of the skin during wound healing depends on plasmin and plasminogen, which serve to degrade fibrin depositions in the provisional matrix and thereby facilitate keratinocyte migration. In the current study, we investigated whether plasmin and plasminogen likewise played a role during the development of skin cancer. To test this, we set up a chemically induced skin tumor model in a cohort of mice and found that skin tumor growth in Plg(-/-) male mice was reduced by 52% compared with wild-type controls. Histological analyses suggested that the growth-restricting effect of plasminogen deficiency was due to thrombosis and lost patency of the tumor vasculature, resulting in tumor necrosis. The connection between plasmin-dependent fibrinolysis, vascular patency, and tumor growth was further substantiated as the effect of plasminogen deficiency on tumor growth could be reverted by superimposing heterozygous fibrinogen deficiency on Plg(-/-) mice. Tumors derived from these Fib(-/+);Plg(-/-) mice displayed a significantly decreased level of tumor thrombosis compared with Plg(-/-) mice. In summary, these data indicate that plasmin-driven fibrinolysis facilitates tumor growth by maintaining patency of the tumor vasculature.

Topics: Animals; Extracellular Matrix; Female; Fibrin; Fibrinogen; Fibrinolysin; Fibrinolysis; Gene Expression Regulation, Neoplastic; Humans; Laminin; Male; Mice; Mice, Knockout; Neoplasms, Experimental; Ovariectomy; Sex Factors; Skin Neoplasms; Thrombosis

In primary human melanoma, the membrane-type matrix metalloproteinase, MT3-MMP, is overexpressed in the most aggressive nodular-type tumors. Unlike MT1-MMP and MT2-MMP, which promote cell invasion through basement membranes and collagen type I-rich tissues, the function of MT3-MMP in tumor progression remains unclear. Here, we demonstrate that MT3-MMP inhibits MT1-MMP-driven melanoma cell invasion in three-dimensional collagen, while yielding an altered, yet MT1-MMP-dependent, form of expansive growth behavior that phenocopies the formation of nodular cell colonies. In melanoma cell lines originating from advanced primary or metastatic lesions, endogenous MT3-MMP expression was associated with limited collagen-invasive potential. In the cell lines with highest MT3-MMP expression relative to MT1-MMP, collagen-invasive activity was increased following stable MT3-MMP gene silencing. Consistently, MT3-MMP overexpression in cells derived from less advanced superficially spreading melanoma lesions, or in the MT3-MMP knockdown cells, reduced MT1-MMP-dependent collagen invasion. Rather than altering MT1-MMP transcription, MT3-MMP interacted with MT1-MMP in membrane complexes and reduced its cell surface expression. By contrast, as a potent fibrinolytic enzyme, MT3-MMP induced efficient invasion of the cells in fibrin, a provisional matrix component frequently found at tumor-host tissue interfaces and perivascular spaces of melanoma. Since MT3-MMP was significantly upregulated in biopsies of human melanoma metastases, these results identify MT3-MMP as a matrix-dependent modifier of the invasive tumor cell functions during melanoma progression.

Topics: Catalysis; Cell Line, Tumor; Cell Membrane; Collagen; Disease Progression; Fibrin; Gene Expression Regulation, Neoplastic; Gene Silencing; Humans; Lymphatic Metastasis; Matrix Metalloproteinase 16; Melanoma; Neoplasm Invasiveness; Polymerase Chain Reaction; Prognosis; Skin Neoplasms

Two hundred and four accessible cases of malignant melanoma from the Grampian region of Scotland, collected over a period of 4 years, with minimum follow-up of 2 years, were studied for coagulation factors and vascular endothelial growth factor (VEGF) expression as potential prognostic markers. The aim was to allow comparison with previous work using microvessel density on the same cases.. Immunohistochemistry for VEGF, tissue factor (TF), fibrin and protease-activated thrombin receptor (PAR)-1 in 204 cases of melanoma was performed, and intensity of expression scored. Chalkley microvessel counts (MVD) were obtained for the tumour edge. TF expression and presence of fibrin correlated well with Breslow thickness and ulceration, reaching statistical significance, but surprisingly not for metastatic recurrence. Fibrin was variably present in over half the cases, located at the invasive edge, ulcerated surface and between tumour cell surfaces. In a few cases fibrin was within tumour cells, typically co-located with melanin and confirmed by electron microscopy. In contrast, immunohistochemistry for PAR-1 produced statistically significant results, correlating expression with Breslow thickness (P < or = 0.001), ulceration (P = 0.001) and recurrence (P < or = 0.005). Intensity of reactivity of VEGF correlated significantly with Breslow thickness, Clark level, ulceration and MVD, but not for metastatic recurrence.. It appears paradoxical that VEGF expression is not more predictive of recurrence, but even low expression may be sufficient for tumour angiogenesis and other factors must govern tumour aggression. Antagonism of VEGF may still prove a successful adjunct in future therapeutic trials. Both MVD and PAR-1 can be used as adjuncts to Breslow thickness and ulceration as prognostic indicators for melanoma, as they appear to give independent information for all thicknesses. PAR-1 expression is the best antibody marker of recurrence risk from those studied. It remains to be seen whether this methodology can predict response to novel antiangiogenic therapies currently entering trial.

Topics: Biomarkers, Tumor; Fibrin; Humans; Immunohistochemistry; Melanocytes; Melanoma; Melanosomes; Microscopy, Electron, Transmission; Neoplasm Recurrence, Local; Neovascularization, Pathologic; Prognosis; Receptor, PAR-1; Skin Neoplasms; Thromboplastin; Vascular Endothelial Growth Factor A

Although attempts to develop any viable chemotherapeutic approaches to combat metastatic cancers have largely failed, potential genetic targets to halt metastatic progression continue to be identified. As drugs are developed to address these targets, there is a need for high-throughput systems that accurately reproduce in vivo microenvironments to gauge their efficacy. Accordingly, we have developed a three-dimensional in vitro culture system representative of the environment present upon secondary metastasis to quantitatively measure tumor cell invasion in this setting three-dimensionally. Culturing melanomas of different metastatic capacities within the system showed that each cell type invades the matrix in a manner commensurate to its known metastatic potential in vivo. Moreover, the developed quantitative schemes were put to use to characterize the effect of microenvironmental influences (i.e., matrix components, interstitial cell presence) on planar and vertical melanoma invasion. We propose this novel, quantitative system as a useful tool to assess the effects of pharmacologic and/or microenvironmental influences on tumor cell invasion at a metastatic site.

Topics: Collagen; Epidermal Cells; Epidermis; Extracellular Matrix; Fibrin; Green Fluorescent Proteins; Humans; Image Processing, Computer-Assisted; Melanoma; Models, Biological; Neoplasm Invasiveness; Skin Neoplasms

Pleomorphic hyalinizing angiectatic tumor (PHAT) of the soft tissue is a rare distinctive tumor listed as a benign neoplasm in the new World Health Organization classification. It may recur and most reported recurrent tumors retained the typical morphological appearance of PHAT; rare tumors recurred with the appearance of a sarcoma. Reported herein is an additional example of recurrent PHAT, but in contrast to the previously described cases the present tumor morphologically qualified as a sarcoma from the very beginning; it recurred as a high-grade myxofibrosarcoma. A 76-year-old woman presented with a solitary subcutaneous tumor in the axilla that was surgically removed. Seven months later, the patient experienced a local recurrence. Microscopically, the typical features of PHAT were identified in the initial lesion, namely hyalinized, fibrin-containing vessels and pleomorphic stromal cells; there were areas of hemorrhage and necrosis. Additionally, peripherally located areas of the tumor manifested highly pleomorphic cells with frequent atypical mitoses, producing a sarcomatous appearance. The mitotic index in the sarcomatous part was 1/10 high-power fields (HPF). Hyalinized, fibrin-containing vessels were absent in these sarcomatous areas, and the stroma was myxoid. The recurrent lesion was composed of large highly pleomorphic oval, round, spindled or bizarre cells with a high mitotic rate, ranging from 3/10 HPF to 7/10 HPF. The neoplastic cells were arranged haphazardly in a myxoid matrix. Hyalinized, fibrin-containing vessels typical for PHAT were absent. PHAT may be more aggressive than previously thought, and PHAT may encompass a morphological spectrum of the lesion ranging from benign to malignant.

Topics: Aged; Dermatofibrosarcoma; Female; Fibrin; Humans; Hyalin; Necrosis; Neoplasm Recurrence, Local; Sarcoma; Skin; Skin Neoplasms

We postulated that skin metastases and cutaneous local recurrences from breast adenocarcinoma show different growth patterns with distinct angiogenic profiles.. Fifty-one surgically resected dermal breast cancer deposits were evaluated for growth pattern, E-cadherin expression, presence of necrosis and a fibrotic focus, fibrin deposition, carbonic anhydrase IX expression (CA IX), microvessel density, endothelial cell proliferation and blood vessel immaturity. Growth patterns were infiltrative, with carcinoma cells infiltrating the dermis without significant disturbance of the pre-existing architecture, expansive, meaning that a nodule of carcinoma cells and desmoplastic tissue pushed aside the pre-existing dermal structures, or mixed. All lobular carcinomas showed an infiltrative growth and lacked membranous E-cadherin expression. Different growth patterns in the ductal carcinomas were not correlated with differences in E-cadherin expression. The presence of necrosis and/or a fibrotic focus and the expression of the hypoxia marker CA IX were significantly associated with an expansive growth. Fibrin was present in all expansive deposits and less frequently in the other growth patterns. There was a positive association between fibrin deposition, CA IX expression and microvessel density. The latter was significantly higher in the expansive and mixed growth patterns than in the infiltrative pattern. Endothelial cell proliferation was highest in the expansive growth pattern and was positively correlated with the presence of a fibrotic focus and with fibrin deposition. The maximum percentage of immature blood vessels was higher in the expansive and mixed growth patterns than in the infiltrative one.. The recognition of different subgroups of cutaneous breast cancer deposits with different degrees of hypoxia-driven angiogenesis may have important implications for the usefulness of anti-angiogenic therapy.

Topics: Adenocarcinoma; Antigens, Neoplasm; Biomarkers, Tumor; Breast Neoplasms; Cadherins; Carbonic Anhydrase IX; Carbonic Anhydrases; Cell Hypoxia; Female; Fibrin; Fluorescent Antibody Technique, Indirect; Humans; Immunoenzyme Techniques; Microcirculation; Necrosis; Neoplasm Proteins; Neovascularization, Pathologic; Skin; Skin Neoplasms

Malignant angioendotheliomatosis is a rare intravascular (angiotropic) lymphoma. Patients most often present with cutaneous or central nervous system findings. We describe three patients with malignant angioendotheliomatosis involving the skin. The initial lesions in each were tender, indurated nodules on the lower extremities, resembling inflammatory panniculitis. Skin biopsies and immunohistochemical studies from all patients confirmed intravascular B-cell lymphoma. Two patients had visceral involvement, and molecular genetics studies showed clonal immunoglobulin gene rearrangement in one. Electron microscopy in this case showed increased fibrin and atypical lymphocytes within blood vessels. Malignant angioendotheliomatosis is a monoclonal intravascular lymphoma, usually of B-cell phenotype. Occlusion of small blood vessels with lymphoid cells, fibrin, and degenerating cellular debris causes the cutaneous lesions. An excisional biopsy through the depth of subcutaneous tissue may be necessary to confirm the diagnosis of malignant angioendotheliomatosis.

Topics: Aged; Aged, 80 and over; Blood Vessels; Female; Fibrin; Gene Rearrangement; Genes, Immunoglobulin; Humans; Lymphocytes; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Male; Microscopy, Electron; Middle Aged; Molecular Biology; Phenotype; Skin Neoplasms

A 25-year-old man had a 5-year history of multiple tender lesions of both extremities and trunk. Biopsy found an encapsulated subcutaneous nodule composed of numerous small, well-formed blood vessels, some filled with fibrin thrombi. This lesion was made up > 99.9% of blood vessels with only a minimal amount of adipose tissue. We believe our case is in the spectrum of angiolipoma even though it is made up almost entirely of a vascular component. These tumors may be confused with other multiple or eruptive vascular lesions that have a more ominous clinical course. This case is being reported to stress that multiple or eruptive "vascular" lesions do not always reflect an underlying immunosuppression or malignancy.

Topics: Adipose Tissue; Adult; Angiolipoma; Diagnosis, Differential; Fibrin; Humans; Male; Skin Neoplasms; Thrombosis

Topics: Actin Cytoskeleton; Collagen; Dermatofibrosarcoma; Female; Fibrin; Fibroma; Giant Cell Tumors; Humans; Infant; Skin Neoplasms

Topics: Bone and Bones; Fibrin; Humans; Melanocytes; Melanoma; Osteosarcoma; Skin Neoplasms

In many fields of surgery the use of highly concentrated human fibrinogen, which forms a fibrin clot when thrombin is added, is gaining increasing importance for tissue adhesion. A number of experimental and clinical reports on fibrin sealing have been published during recent years. The question underlying our present investigations is as follows: What happens to the tissue adhesive after its application to a wound in clinical use, i.e., how much time is required for complete resorption of the seal due to fibrinolytic processes? Skin graftings of the face (required to close defects caused by the excision of basal or spinal cell carcinomas) were performed by glueing rhomboid flaps or full thickness skin grafts to the wounds with the tissue adhesive to which 125I-marked fibrinogen has been added. Activity counts were recorded daily and CPM were plotted versus time to obtain summation curves. The physiological processes of fibrin stabilization and fibrinolysis are extensively discussed as both factors influence the tissue adhesive and thus have to be accounted for in clinical practice.

Topics: Aged; Carcinoma, Basal Cell; Facial Neoplasms; Factor XIII; Fibrin; Fibrinogen; Fibrinolysis; Humans; Male; Skin Neoplasms; Surgical Flaps; Tissue Adhesives; Wound Healing

Topics: Antibodies, Neoplasm; Body Fluids; Complement Fixation Tests; Complement System Proteins; Female; Fibrin; Fibrinogen; Fluorescent Antibody Technique; Humans; Immunoglobulin G; Immunoglobulin M; Keratoacanthoma; Male; Neoplasm Regression, Spontaneous; Skin Neoplasms

Topics: Adult; Aged; Aneurysm; Aortic Aneurysm; Arteriosclerosis; Blood Cell Count; Blood Coagulation; Blood Platelets; Buttocks; Cell Survival; Chromium Radioisotopes; Chronic Disease; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrinogen; Hemangioma; Humans; Iodine Radioisotopes; Middle Aged; Purpura, Thrombocytopenic; Skin Neoplasms; Syndrome; Thrombosis

Topics: Anemia; Animals; Blood Platelets; Disease Models, Animal; Erythrocytes, Abnormal; Fibrin; Hemangioma; Mice; Microscopy, Electron, Scanning; Neoplasm Transplantation; Neoplasms, Experimental; Purpura, Thrombocytopenic; Skin; Skin Neoplasms; Transplantation, Homologous

Topics: Fibrin; Fibrinolysin; Geriatrics; Humans; Neoplasm Metastasis; Neoplasms; Skin Neoplasms; Stomach Neoplasms; Tongue Neoplasms; Toxicology

Topics: Fibrin; Fibrin Foam; Humans; Neoplasms; Neoplasms, Radiation-Induced; Radiation Injuries; Radiodermatitis; Research; Skin Neoplasms