Stromal reaction in cancer tissue: Pathophysiologic significance of the expression of matrix-degrading enzymes in relation to matrix turnover and immune/inflammatory reactions

Cancers are characterized by invasive growth and distant metastasis. Cancer cells not only destroy the pre-existing extracellular matrix, but cancer invasion per se usually induces new matrix formation by activation of stromal cells; that is, desmoplastic reaction. This process includes both matrix production and degradation; that Is, the remodeling process. The similarity between desmoplastic reactions in cancer stroma and the wound healing process has already been pointed out, and it has been well documented that matrix-degrading processes are actively involved In the wound healing process. A recent study revealed that most matrix-degrading enzymes, generally considered to be one of the main mechanisms of cancer invasion and metastasis, are originated from stromal cells. Based on these preconditions, the present review postulates that the abundant expression of matrix-degrading enzymes by fibroblasts, coupled with the abundant expression of type I procollagen, is involved in the matrix remodeling processes occurring in cancer stroma; that is, the mechanism similar to the wound healing process. Next, macrophages distributed along the invasive margin are known to express matrix-degrading enzymes/factors. Data from past studies of colon carcinoma indicate that the tissue expression of matrix metalloproteinase-9 and urokinase-type plas-mlnogen activator receptor Is inversely associated with simultaneous liver metastasis and infiltrating growth pattern. Previous clinicopathologic data have indicated that immune/Inflammatory cells are one of the factors for a favorable prognosis. This suggests that the expression of matrix-degrading enzymes/factors by these host cells may be involved in host immune/inflammatory reactions, and that the net function of these cells can be defensive towards the host. Data from past studies of colon carcinoma on the expression of the intercellular adhesion molecule-1 suggest that the interaction between macrophages, lymphocytes, and the phenotypes of venules distributed along the Invasive margin, further support the pro-inflammatory milieu there. Therefore, the matrix degradation process in cancer tissue is multifunctional: besides the Involvement in cancer invasion and metastasis, the matrix degradation process is also involved in the tissue remodeling process and in the immune/inflammatory reaction occurring in the stroma.     

Quercetin inhibits the invasion and mobility of murine melanoma B16-BL6 cells through inducing apoptosis via decreasing Bcl-2 expression

Quercetin has been known to have anti-tumor and anti-oxidation activities. In the present study, we have investigated its in vitro anti-metastatic activity. Quercetin inhibited the invasion and mobility of murine melanoma B16-BL6 cells in a dose-dependent manner but did not affect their adhesion to either laminin, fibronectin, or type VI collagen. Moreover, quercetin significantly inhibited the proliferation of B16-BL6 cells only in the case of time incubation longer than 48 h. Quercetin dose-dependently decreased the cell rates in S and G2–M phases of cell cycle. The effect of quercetin to cause a remarkable apoptosis of B16-BL6 cells was also demonstrated by flow cytometric assay as well as DNA fragmentation with a typical 180-bp ladder band in agarose electrophoresis and a quantitative analysis. Furthermore, quercetin markedly inhibited the expression of anti-apoptotic protein Bcl-2 but hardly influenced Bcl-X_L. These results suggest that the inhibition of quercetin on invasiveness and migration of B16-BL6 cells are closely associated with the arrest of cell cycle as well as the induction of apoptosis by decreasing the Bcl-2 expression. This revised version was published online in July 2006 with corrections to the Cover Date.     

Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): diagnosis by fine-needle aspiration

Sinus histiocytosis with massive lymphadenopathy (SHML) is a rare idiopathic proliferative disorder of histiocytes with characteristic morphologic features. We describe a case of SHML occurring in a 14-yr-old black male, in whom the diagnosis was made by fine-needle aspiration of a cervical lymph node. Cytologic features included increased numbers of large histiocytes associated with a polymorphous, cellular background composed of benign lymphocytes, plasma cells, and polymorphonuclear leukocytes. Lymphophagocytosis was a prominent feature. Extranodal involvement of the larynx was documented by surgical biopsy; there was no other extranodal disease. One year after diagnosis, the patient is clinically well, with no residual lymphadenopathy.     

Attachment, invasion, chemotaxis, and proteinase expression of B16-BL6 melanoma cells exhibiting a low metastatic phenotype after exposure to dietary restriction of tyrosine and phenylalanine

We previously reported that low levels of tyrosine (Tyr) and phenylalanine (Phe) alter the metastatic phenotype of B16-BL6 (BL6) murine melanoma and select for tumor cell populations with decreased lung colonizing ability. To more specifically characterize the effects of Tyr and Phe restriction on the malignant phenotype of BL6, we investigated in vitro attachment, invasion, proteinase expression, and chemotaxis of high and low metastatic BL6 variants. High metastatic variant cells were isolated from subcutaneous tumors of mice fed a nutritionally complete diet (ND cells) and low metastatic variant cells were isolated from mice fed a diet restricted in Tyr and Phe (LTP cells). Results indicate that attachment to reconstituted basement membrane (Matrigel) was significantly reduced in LTP cells as compared to ND cells. Attachment to collagen IV, laminin, and fibronectin were similar between the two variants. Invasion through Matrigel and growth factor-reduced Matrigel were significantly decreased in LTP cells as compared to ND cells. Zymography revealed the presence of M _r 92 000 and M _r 72 000 progelatinases, tissue plasminogen activator, and urokinase plasminogen activator in the conditioned medium of both variants; however, there were no differences in activity of these secreted proteinases between the two variants. Growth of the variants on growth factor-reduced Matrigel similarly induced expression of the M _r 92 000 progelatinase. The variants exhibited similar chemotactic responses toward laminin. However, the chemotactic response toward fibronectin by LTP cells was significantly increased. MFR5, a monoclonal antibody which selectively blocks function of the ₅ chain of the ₅ß₁ integrin, VLA-5, decreased the chemotactic response toward fibronectin of ND cells by 37%; the chemotactic response by LTP cells was reduced by 49%. This effect was specific for fibronectin-mediated chemotaxis since the chemotaxis toward laminin and invasion through Matrigel were not altered by the presence of MFR5. The surface expression of VLA-5 was significantly increased in LTP cells as compared to ND cells by flow cytometric analysis. These observations suggest that limitation of Tyr and Phe either directly modifies BL6 or selects for subpopulations with altered in vitro invasion, chemotaxis, and integrin expression.     

HLA antigens are candidate markers for prediction of lymph node metastasis in gastric cancer

We investigated the association between human leucocyte antigen (HLA) antigens and lymph node metastasis in 724 gastric cancer patients. Among patients who had poorly differentiated adenocarcinoma with or without HLA-DR4 antigen, lymph node metastasis was detected in 80.8 and 54.9%, respectively (relative risk (RR)=3.5, P = 0.0005, corrected P = 0.0285). It was more common in patients with a family history of cancer death (RR = 7.7). Among signet ring cell carcinoma patients with or without HLA-1152 antigen, lymph node metastasis was detected in 57.7 and 19.7%, respectively (RR =5.6, P=0.0001, corrected P=0.0086). It was more common in patients who were smokers (RR = 8.3). Our findings suggest that HLA-DR4 and HLA-1152 antigens are associated with lymph node metastasis in gastric cancer.     

Expression of ICAM-1, VCAM-1 and ELAM-1 in angiofollicular lymph node hyperplasia (Castleman''s disease): evidence for dysplasia of follicular dendritic reticulum cells

The inducible adhesion molecules mediate important functions in the lymphoid tissues. We have investigated the expression of intercellular adhesion molecule 1 (ICAM-1), endothelial leucocyte adhesion molecule 1 (ELAM-1), vascular cell adhesion molecule 1 (VCAM-1), and platelet endothelial cell adhesion molecule (PECAM/CD31), using immunocytochemistry on cryostat sections of five lymph nodes from patients with Castleman's disease of the hyaline-vascular type. All five cases were characterized by marked hyperplasia of follicular dendritic reticulum cells, which were extensively present even in the mantle zone. Hyperplastic follicular dendritic reticulum cells showed marked expression of VCAM-1, and weak expression of ICAM-1. In two cases, several dysplastic giant cells with aberrant, polyploid nuclei showed aberrant expression of ELAM-1, an endothelium-restricted molecule. Dysplastic giant cells were positive with DRC-1 (an antibody to dendritic reticulum cells), VCAM-1 and occasionally ICAM-1, were negative for the endothelial cell markers factor VIII-related antigen and CD31 and were non-proliferating (Kl-67-). Cells positive for ICAM-1 or VCAM-1 were rare in the interfollicular areas. In all cases vascular hyperplasia was prominent, but endothelial cells were poorly activated in terms of expression of inducible adhesion molecules and of HLA-DR antigens. The possibility that dysplastic follicular dendritic reticulum cells have a pathogenetic role in Castleman's disease is discussed.     

A new pseudo-peptide of Arg-Gly-Asp (RGD) with inhibitory effect on tumor metastasis and enzymatic degradation of extracellular matrix

A series of pseudo-peptide analogs of the Arg-Gly-Asp (RGD) sequence of fibronectin have been synthe-sized, and their anti-metastatic effects in mice and inhibitory effects on tumor cell invasion in vitro have been examined. The partially modified retro pseudo-peptide of RGD, R_rev-COCH₂CO-D (FC-63), was more effective in inhibiting tumor metastasis than the original RGDS peptide. Replacement of the malonyl moiety of FC-63 with a carboxyethylene linkage (R_rev-COCH₂CH₂-D, FC-303 ) achieved more potent inhibition of lung metastasis of melanoma cells than FC-63. Among the analogs, FC-336, a p-xylylendiamine derivative having two FC-303 moieties, showed the most potent inhibitory effect on experimental lung metastasis produced by i.v. co-injection with B16-BL6 melanoma or colon 26 M3.1 cells in a dose-dependent manner. Multiple administrations of FC-336 after tumor inoculation also showed efficient therapeutic potency against spontaneous lung metastasis of B16-BL6 melanoma in mice. Furthermore, FC-336 effectively inhibited the invasion, migration and adhesion of tumor cells in vitro, but its inhibitory effects were not more than those of RGDS peptide. Zymography analysis revealed that FC-336 inhibited the degradation of gelatin substrate by matrix metalloproteinases (MMPs) produced by tumor cells, while the RGDS peptide did not affect the enzymatic degradation. These findings indicate that the pseudo-peptides of the RGD sequence, possessing the inhibitory property of the degradation by MMPs differently from original RGD-containing peptides, may be advantageous and useful in preventing tumor metastasis. © Rapid Science 1998     

Investigation and management of the neck lump

A neck lump is a common presenting sign in both the paediatric and adult population and may represent a broad range of benign or malignant diagnoses. The appropriate initial assessment, investigation and management is key to delivering appropriate treatments and to avoid missing potentially serious diagnoses. There is a range of imaging modalities available to the treating clinician and huge variability in the appropriate surgical or non-surgical management of disease. In this article we discuss the approach to the assessment of patients with a neck lump, including the history and examinations which should take place. We discuss the imaging modalities which are most appropriate for each condition and the range of management options available. Both common and rarer diagnoses are discussed through the course of the review.     

Axillary management based on American college of surgeons oncology group Z0011 criteria makes it possible to omit intraoperative diagnosis of sentinel lymph nodes in early breast cancer patients

The ACOSOG Z0011 trial has resulted in the omission of axillary lymph node dissection (ALND) in early breast cancer patients with one or two metastatic sentinel lymph nodes (SLNs). There has been increasing interest in the necessity of intraoperative assessment of SLNs in patients treated based on the Z0011 criteria. We evaluated the utility of intraoperative assessment in these eligible patients. A total of 1396 patients were treated following the Z0011 criteria from April 2012 to December 2019. We examined the proportion and clinicopathological features of patients who underwent ALND due to three or more metastatic SLNs and the sensitivity of intraoperative assessment. Only 16 (1.1%) patients had three or more metastatic SLNs diagnosed by intraoperative assessment, and they immediately underwent ALND. Of the clinicopathological factors, high clinical tumor stage (p = 0.002) and high Ki-67 labeling index value (p = 0.056) were more likely to be associated with the presence of three or more metastatic SLNs. The major independent risk factor for three or more metastatic SLNs was high clinical tumor stage (OR 3.94 [95% CI 1.42–11.0]; p = 0.009). Intraoperative assessment had low sensitivity (70.5%) and a high false-negative rate (29.5%) in detecting SLN metastases. The main finding of our study was the small proportion of patients who required ALND due to three or more metastatic SLNs according to the Z0011 criteria. The Z0011 strategy enables intraoperative assessment of SLNs to be omitted in early breast cancer patients.