Lining Xie

Clinicopathologic and prognostic significance of SATB1 in cutaneous malignant melanoma

BACKGROUND Special AT-rich sequence-binding protein-1 (SATB1), a new type of gene regulator, has been reported to be expressed in several human cancers and may have malignant potential. However, no data on SATB1 expression and its relationship to tumor progression in cutaneous malignant melanoma (CMM) has yet been reported. OBJECTIVE We examined the immunohistochemical expression of SATB1 in CMM to determine whether it could serve as a prognostic marker. METHODS A total of 97 samples of primary CMM and controls were immunostained for SATB1. The following clinicopathologic variables were evaluated: age, gender, subtype, SATB1 expression, Breslow thickness, Clark level, presence of ulceration, lymph node metastasis, distant metastasis, and survival. Statistical analyses were performed to assess for associations. Several parameters were analyzed for survival using the Kaplan-Meier method and Cox proportional-hazards model. RESULTS Forty cases (85.1%) of CMM showed positive staining for SATB1 by immunohistochemistry. The intensity of SATB1 staining was significantly higher in CMM than in nevus NV and normal skin (NS) (P < 0.01). High SATB1 expression was significantly correlated with Breslow thickness, Clark level, mortality, presence of ulceration, and lymph node metastasis (P < 0.01). Moreover, Kaplan-Meier analysis revealed that SATB1 overexpression was significantly associated with worse survival (P < 0.01). Further univariate analysis and multivariate regression analysis indicated that SATB1 expression was an independent prognostic marker for CMM (P = 0.03). CONCLUSIONS The overexpression of SATB1 correlated with metastatic potential of CMM and is a novel independent prognostic marker for predicting outcome.

Expression of CD10 predicts tumor progression and unfavorable prognosis in malignant melanoma

BACKGROUND CD10 expression in malignant melanoma (MM) has been reported to increase according to tumor progression and metastasis; however, its association with patient outcome has not been clarified. OBJECTIVE We examined the immunohistochemical expression of CD10 in MM to determine whether or not it could serve as a marker for tumor progression and prognosis. METHODS A total of 64 formalin-fixed, paraffin-embedded samples of primary MM were immunostained for CD10. Similarly, 40 samples of melanocytic nevus and 20 of metastatic MM were analyzed for comparison. The following clinicopathologic variables were evaluated: age, gender, histologic type, tumor site, Breslow thickness, Clark level, the presence or absence of ulceration and tumor-infiltrating lymphocytes, and survival. Statistical analyses were performed to assess for associations. Several parameters were analyzed for survival using the Kaplan-Meier method and Cox proportional hazards model. RESULTS Immunohistochemical analysis revealed that 34 of 64 cases (53%) of primary MM expressed CD10, compared with 15 of 20 cases (75%) of metastatic MM and only 4 of 40 cases (10%) of nevus. There was a significant positive relationship between CD10 expression and Breslow thickness, Clark level, and ulceration. Univariate analysis revealed 4 significant factors for shorter survival periods: CD10 expression, high Breslow thickness, high Clark level, and the presence of ulceration (P < .01 each). In multivariate analysis, CD10 expression was revealed to be a statistically significant and independent prognostic factor. LIMITATIONS The major limitation was the small sample size. CONCLUSION CD10 expression may serve as a progression marker and can predict unfavorable prognosis in patients with MM.

Cathepsin K-upregulation in fibroblasts promotes matrigel invasive ability of squamous cell carcinoma cells via tumor-derived IL-1α

BACKGROUND Cathepsin K (CTSK), a cysteine protease with strong collagenolytic properties, is involved in extracellular matrix turnover. In the previous studies, CTSK expression was detected in peritumoral fibroblasts (Fbs) around squamous cell carcinoma (SCC), but not in those surrounding benign epidermal tumors. However, the mechanism governing CTSK expression in epidermal tumors remains unclear. OBJECTIVE To study the regulatory mechanisms of fibroblastic CTSK expression in the SCC-stromal interaction. METHODS We examined dynamic interactions of Fbs with tumorigenic SCC cells (A431 and A253) or normal human keratinocytes. RESULTS SCC cells and normal keratinocytes did not synthesize CTSK, while Fbs constitutively expressed CTSK. When cocultured, SCC cells upregulated fibroblastic CTSK expression more potently than did normal keratinocytes, which was mainly attributable to SCC-derived IL-1α. Coculturing Fbs with SCC cells significantly augmented the matrigel invasive ability of SCC cells, which was downregulated when cocultured with CTSK knockdown Fbs or in the presence of neutralizing anti-IL-1α antibody. CONCLUSION The CTSK-upregulated Fbs generated by SCC-derived IL-1α may play a crucial role in the progression and invasion of SCC.

CD10-bearing fibroblasts may inhibit skin inflammation by down-modulating substance P

Substance P (SP) is a multipotent neuropeptide that affects the proliferation, activation and motility of keratinocytes and fibroblasts (Fbs). SP in pulmonary and synovial cells is degraded by CD10, a 90- to 110-kDa cell surface zinc-dependent metalloprotease. However, the expression and function of CD10 in human dermal Fbs have not yet been investigated in vivo and in vitro specifically with reference to SP. Our immunohistologic study revealed moderate to strong fibroblastic CD10 expression in the majority of psoriasis vulgaris (16/16), chronic eczema (15/16), lichen planus (18/20) and atopic dermatitis (4/5). Keratinocytes showed no CD10 expression in vivo and in vitro. Cultured Fbs constitutively expressed CD10 and SP. CD10 expression was augmented by external interleukin (IL)-1β and IL-22, but not by IL-8 and IL-17A in Fbs. SP production was enhanced in CD10 knockdown-Fbs (CD10ND-Fbs) compared with control-Fbs. In the presence of IL-1β or IL-22, the enhancement of SP production was more prominent in CD10ND-Fbs than in control-Fbs, suggesting the down-modulating activity of CD10 on SP in cytokine-mediated inflammation. In conclusion, fibroblastic CD10 expression may down-regulate skin inflammation by degrading SP or reducing its level in the dermal microenvironment.

Stromal expression of cathepsin K in squamous cell carcinoma.

Background  Cathepsin K (CTSK), a cysteine protease with strong collagenolytic and elastolytic properties involved in extracellular matrix turnover, may be produced by neoplastic cells as well as stromal macrophages and fibroblasts. Its expression is suggested as associated with increased invasive and metastatic potential.

Levels of the EMT‐related protein Snail/Slug are not correlated with p53/p63 in cutaneous squamouscell carcinoma

The contribution of the E‐cadherin transcriptional repressors Snail and Slug to invasion and metastasis has strengthened the evidence for the importance of epithelial‐mesenchymal transition (EMT) in carcinoma progression. However, to the best of our knowledge, no study has described the immunohistochemical staining of the EMT‐related proteins Snail/Slug in skin tumors and the correlation between Snail/Slug and tumor suppressor p53/p63.

Aberrant expression of CD10 in ground-glass-like multinucleated giant cells of multicentric reticulohistiocytosis

Dear Editor, Multicentric reticulohistiocytosis (MRH) is a rare systemic disorder characterized by an extensive papulonodular cutaneous eruption as well as severe, sometimes destructive, arthropathy. Arthritis and joint damage are usually progressive. Most patients have interphalangeal joint involvement of the hands, but there have also been sporadic cases of involvement of other joints including the knees, shoulders, wrists, hips, ankles, feet and elbows, in decreasing frequency. The disabling arthritic process progresses rapidly in the early stage and then decreases in intensity to become less active over the ensuing 8–10 years. The diagnosis of MRH is based on the characteristic histopathological findings, presenting multinucleated giant cells of a foreign-body type, with irregular size and shape reaching 50–100 lm in diameter. The cytoplasm of the giant cells is slightly eosinophilic and has a finely granulated ground-glass appearance or a foamy, vacuolated appearance. The pathogenesis of MRH is unknown; however, aberrant proliferation of the histiocytic population is postulated in response to monokines, cytokines and other secretory products that promote macrophage proliferation and phagocytosis. In addition, the biological nature and pathogenetic significance of the groundglass-like multinucleated giant cells remain largely unknown. CD10 is a 90to 110-kDa cell surface zinc-dependent metalloprotease also known as neutral endopeptidase (EC 3.4.24.11), enkephalinase, neprilysin and common acute lymphoblastic leukemia antigen. CD10 was originally reported as a subclassification marker for lymphomas ⁄ leukemias of Band T-cell lineage. CD10 has been detected in the peritumoral fibroblast-like stromal cells within the

Nerve growth factor, brain-derived neurotrophic factor and their high-affinity receptors are overexpressed in extramammary Paget's disease

Background: Neurotrophin (NT) systems appear to play important roles in the pathogenesis of several tumors, but their expression in extramammary Pagets disease (EPD) has not been investigated.

CD10‐bearing fibroblast inhibits matrigel invasive potency of interleukin‐1α‐producing squamous cell carcinoma by diminishing substance P levels in the tumor microenvironment

CD10 is a neutral endopeptidase, which cleaves various peptide substrates including substance P. CD10 expression has been detected in peritumoral fibroblasts (Fb) within the invasive area of various cancers such as squamous cell carcinoma (SCC). However, the biological significance of CD10‐bearing Fb remains largely unknown. We examined dynamic interactions of Fb with tumorigenic A431 SCC cells or non‐tumorigenic HaCaT squamous cells. The SCC and HaCaT cells did not synthesize CD10, while Fb constitutively expressed CD10. When co‐cultured, SCC markedly upregulated fibroblastic CD10 expression compared with HaCaT, which was mainly attributable to SCC‐derived interleukin‐1α (IL‐1α). Both SCC and Fb autonomously secreted substance P, which eventually enhanced the invasive capacity of SCC in a matrigel invasion assay by upregulating matrix metalloproteinase (MMP)‐1 and MMP‐2, but not MMP‐9. Transfection of siRNA for CD10 successfully knocked down the CD10 expression in Fb (CD10ND‐Fb). In the presence of CD10ND‐Fb, substance P levels in supernatants as well as MMP production and the invasive potency of SCC were significantly augmented compared with control scramble RNA‐transfected Fb. We also transfected CD10 vector to Fb and found that the matrigel invasive ability of SCC cells was downregulated co‐cultured with CD10 vector‐transfected Fb rather than empty vector‐transfected Fb. In conclusion, the CD10‐bearing Fb generated by SCC‐derived IL‐1 inhibited the invasive capacity of SCC by diminishing the microenvironmental concentration of substance P. (Cancer Sci 2010; 101: 2570–2578)

Stromal CD10 expression is correlated with invasiveness and proliferation of extramammary Paget disease.

SIR, We thank Heathcote et al. for presenting an unusual series of cases of polymorphic skin eruptions of the pinnae in healthy farm workers following chronic exposure to placental products. This may be a manifestation of Q fever or a similar zoonosis. Q fever is a zoonosis caused by Coxiella burnetii. The name Q fever is derived from ‘query’ to highlight the unexpected aspects of the disease and was first described in Queensland, Australia in 1937 by Derrick. The infection in humans is variable in its severity, clinical expression and natural course (i.e. acute or chronic). Ungulates are the major reservoirs. Animals are infected through aerosols and may shed Coxiella in faeces, urine, milk and birth products. Humans are usually infected by aerosol exposure. Major outbreaks have been related to sheep and are partly seasonal and related to lambing time. The age and sex distribution of four men ⁄one woman in ‘lambing ears’ is very similar to Q fever in which males tend to manifest the disease despite similar exposure, and middle-aged people are more frequently affected. Coxiella burnetii is a Gram-negative coccobacillus (a gammaproteobacterium). It replicates in the host’s monocytes and macrophages. The developmental cycle of C. burnetii includes macrocellular and microcellular forms and the formation of spore-like bodies. The control of the disease in acute Q fever may be associated with granuloma formation; however, in immunocompetent individuals with previous exposure (as in healthy farmers) granulomas may not be present and this may explain the histological findings of a pandermal perivascular and diffuse, predominantly T cell (CD3) lymphocytic infiltrate. The organism may be subject to antigenic change which would explain why complete immunity may not be transferred year on year. Furthermore, one may hypothesize, partially immune subjects may present with local disease manifestations (not usually described in immunodeficient individuals) at times of antigenic excess, which resolve on removal of the antigenic load. This process is similar to exacerbations of immune complex diseases. Coxiella burnetii in vitro generates a deleted, avirulent mutant also named phase II. This mutant exhibits diagnostic antigens which are more reactive during acute infection. Were these tested for in patients’ serum? We suggest further studies with sequential serological testing for rising titres (to Coxiella as well as other well-known zoonoses) during the next lambing season. Furthermore, may we propose polymerase chain reaction ⁄fluorescent in situ hybridization analysis of biopsy specimens (to satisfy Koch’s postulates)? Vaccination in the light of proven aetiopathogensis may avoid new infections in unexposed individuals.