<b><i>Background:</i></b> Cancer tissues consist of cancer cells and stroma, the latter of which dictates cancer tissue microenvironment. We recently reported that the desmoplastic reaction (DR) pattern at the invasive front in colorectal cancer (CRC) is a promising prognostic indicator. However, the molecular mechanisms of DR formation and contribution to patients’ prognosis remain unclear. <b><i>Summary:</i></b> The tumor tissue microenvironment composed of extracellular matrix (ECM), soluble factors (growth factors/cytokine/cytokine), and stromal cells controls tumor growth and spread. Among stromal cells, cancer-associated fibroblasts (CAFs) play a key role in development of the cancer tissue microenvironment, and they are responsible for DR formation. CAFs express a disintegrin and metalloproteinases (ADAMs), which modulate cancer tissue microenvironmental factors. We isolated CAFs and normal fibroblasts from colon tissues of patients with CRC and characterized them. CAFs showed the increased expression of several ADAM species including ADAM9, ADAM10, ADAM12, and ADAM17, and the expression was further increased on the ECM-coated plates. Our in vitro and in vivo studies using CAFs and CRC cells suggest that ADAM expression is associated with the morphological DR category, and ADAMs may affect cancer malignancy through tumor proliferation in CRC. <b><i>Key Message:</i></b> This review summarizes the present knowledge on ADAMs in cancer and describes our recent findings regarding the molecular biological background of DR mainly by focusing on ADAMs.
The current prospective randomized study was designed to compare the effects of intracavitary (i.c.) chemotherapy vs immunotherapy vs immunochemotherapy for malignant effusion. Between 1992 and 1995, a total of 42 patients with malignant effusion were registered, and 41 patients were eligible for statistical analysis. The primary diseases of the eligible patients included 27 gastric, four colorectal, four pancreatic, three lung, two liver and one oesophageal cancers. The patients with malignant effusion were randomly assigned into one of three i.c. therapeutic regimens: chemotherapy alone with weekly injection of anticancer agents (ACAs: cisplatin, mitomycin-C, adriamycin, etc.) (Group A, n = 13); immunotherapy alone with weekly injection of streptococcal preparation OK-432 (Group B, n = 14); or immunochemotherapy with ACAs and OK-432 (Group C, n = 14). The response of the effusion, patient survival and the kinetics of cytokines in the effusion were compared. There were no differences in the patients' backgrounds. The side-effects of the regimens included pain, anorexia, fever, leucopenia and anaemia and there were no differences in their incidence among the three groups. One patient died after cisplatin (CDDP) administration in Group A. Cytologic examination revealed that tumour cells in the effusion disappeared in 23% of Group A cases, 36% of Group B cases and 36% of Group C cases. The malignant effusion did not disappear in any of the Group A cases; however, the effusion disappeared in 29% of Group B cases and 43% of Group C cases ( P = 0.03, Group A vs Group C). Furthermore, the 50% survival period was 1.6 months for Group A, 2.4 months for Group B and 3.5 months for Group C. The 6-month survival rate was 7% for Group A, 6% for Group B and 34% for Group C, and the 1-year survival rate was 0%, 0% and 17% respectively ( P = 0.048, Group A vs Group C by the log-rank test). The analysis of the cytokine kinetics revealed a prominent increase in the level of interleukin-6 in the effusion in Group C. These results suggest that i.c. immunochemotherapy with OK-432 and ACAs may be more beneficial than i.c. chemotherapy alone or immunotherapy alone. © 1999 Cancer Research Campaign
Mesothelin (MSLN) is a cell-surface glycoprotein present in many cancer types. Its expression is generally associated with an unfavorable prognosis. This study examined the prognostic significance of MSLN expression in different areas of individual colorectal cancers (CRCs) using tissue microarrays (TMAs) by enrolling 314 patients with stage II (T3-T4, N0, M0) CRCs. Using formalin-fixed paraffin-embedded tissue blocks from patients, TMA blocks were constructed. Tissue core specimens were obtained from submucosal invasive front [Fr-sm], subserosal invasive front [Fr-ss], central area [Ce], and rolled edge [Ro] of each tumor. Using these four-point TMA sets, MSLN expression was immunohistochemically surveyed. The area-specific prognostic significance of MSLN expression was evaluated. A deep-learning convolutional neural network algorithm was used for imaging analysis and evaluating our judgment's objectivity. MSLN staining ratio was positively correlated between the manual and machine-learning analyses (= 0.71). The correlation coefficient between Ro and Ce, Ro and Fr-sm, and Ro and Fr-ss was = 0.63, = 0.54, and = 0.61, respectively. Disease-specific survival curves for the MSLN-positive and MSLN-negative groups in Fr-sm, Fr-ss, and Ro were significantly different [five-year survival rates: 88.1% and 95.5% (= 0.024), 85.0 and 96.2% (= 0.0087), 87.8 and 95.5% (= 0.051), and 77.9 and 95.8% (= 0.046) for Fr-sm, Fr-ss, Ce, and Ro, respectively]. The analysis performed using area-specific four-point TMAs clearly demonstrated that MSLN expression in stage II CRC was relatively homogeneous within tumors. Additionally, high MSLN expression showed or tended to 4 show unfavorable prognostic significance regardless of the tumor area.
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