Identification of novel transmembrane proteins in scirrhous-type gastric cancer by the Escherichia coli ampicillin secretion trap (CAST) method: TM9SF3 participates in tumor invasion and serves as a prognostic factor.

OBJECTIVE: Scirrhous-type gastric cancer (GC) is highly aggressive and has a poor prognosis due to rapid cancer cell infiltration accompanied by extensive stromal fibrosis. The aim of this study is to identify genes that encode transmembrane proteins frequently expressed in scirrhous-type GC. METHODS: We compared Escherichia coli ampicillin secretion trap (CAST) libraries from 2 human scirrhous-type GC tissues with a normal stomach CAST library. By sequencing 2,880 colonies from scirrhous CAST libraries, we identified a list of candidate genes. RESULTS: We focused on the TM9SF3 gene because it has the highest clone count, and immunohistochemical analysis demonstrated that 46 (50%) of 91 GC cases were positive for TM9SF3, which was observed frequently in scirrhous-type GC. TM9SF3 expression showed a significant correlation with the depth of invasion, tumor stage and undifferentiated GC. There was a strong correlation between TM9SF3 expression and poor patient outcome, which was validated in two separate cohorts by immunostaining and quantitative RT-PCR, respectively. Transient knockdown of the TM9SF3 gene by siRNA showed decreased tumor cell-invasive capacity. CONCLUSION: Our results indicate that TM9SF3 might be a potential diagnostic and therapeutic target for scirrhous-type GC.

Clinicopathological study of scirrhous hepatocellular carcinoma.

BACKGROUND AND AIMS: Scirrhous hepatocellular carcinoma (SHCC) is characterized by diffuse fibrosis of the tumor, however, its clinicopathological features are not fully clarified. This study aimed to clarify the clinicopathological features of SHCC. METHODS: Among 546 consecutively resected HCC without preoperative anticancer therapies, 25 SHCC were selected for the study and compared with 521 cases without scirrhous as the control. RESULTS: SHCC accounted for 4.6% of cases. On diagnostic imagings, SHCC was frequently misdiagnosed as cholangiocarcinoma (CC), combined HCC-CC or metastatic carcinoma. Overall survival rate was significantly higher than the control. The average (+/-SD) tumor size of SHCC was 3.4 +/- 1.8 cm without significant difference to the control. The majority of SHCC (88%) were located close to the liver capsule. SHCC was characterized by stellate fibrosis (84%), no encapsulation (100%), no necrosis and hemorrhage (100%), intratumoral portal tracts (80%), remarkable lymphocyte infiltration (84%), clear cell change (84%), and hyaline bodies (52%). The number of alpha-smooth muscle actin-positive myofibroblast-like cells (activated stellate cells) in the tumor was about three times more than that in the control. Regarding the developmental mechanism of scirrhous change, a close correlation with unique tumor location and activation of stellate cells was suggested. CONCLUSIONS: SHCC presents with characteristic clinicopathological features and the recognition of SHCC is important for both clinicians and pathologists.

[A case of nonresectable scirrhous type gastric cancer treated by hypertensive subselective chemotherapy with pharmacokinetic modulating chemotherapy].

There have been few effective chemotherapeutic regimens for scirrhous type gastric cancer. A 62-year-old male patient was admitted to our hospital because of anorexia and abdominal discomfort. Gastroendoscopy showed a type 4 advanced gastric cancer in the upper gastric body. Histologic study of biopsy specimens from the tumor revealed poorly differentiated adenocarcinoma. Examination by computed tomography and ultrasonography revealed swollen paraaortic lymph nodes and peritonitis carcinomatosa. The patient was diagnosed as having a nonresectable scirrhous type gastric cancer with peritonitis carcinomatosa and paraaortic lymph node metastasis. This patient was treated weekly with an intraarterial 5-FU (500 mg) and MTX (100 mg) including AT-II by a subcutaneously implanted port system placed into the thoracic aorta. Furthermore, he was administered tegafur/uracil (400 mg/day) 5 days weekly as a pharmacokinetic modulating chemotherapy (PMC). After eight courses of treatment of PMC, paraaortic lymph node swelling and ascites decreased. This chemotherapy produced a partial response in the peritonitis carcinomatosa and paraaortic lymph nodes. This chemotherapy was repeated preoperatively. We reconsidered this case to show indications for operation. The patient died suddenly of acute heart failure before the operation. This therapy was considered an effective treatment for nonresectable gastric cancer.

Effects of transforming growth factor-beta released from gastric carcinoma cells on the contraction of collagen-matrix gels containing fibroblasts.

To investigate the mechanisms underlying contraction of the stomach wall in cases of gastric scirrhous carcinoma, we have developed an in vitro model for gastric cancer, in which both fibroblasts and gastric carcinoma cells are embedded within a collagen matrix. Gastric carcinoma cells of the scirrhous type (KATO-III) but not the nonscirrhous type (MKN-28) markedly enhanced the ability of human intestine, human lip, and mouse kidney fibroblasts to contract collagen gels. KATO-III cells released transforming growth factor-beta (TGF-beta) into culture media in an activated form, whereas the MKN-28 cells produced a latent form. The role of TGF-beta produced by gastric cancer cells from the scirrhous type was clarified by adding TGF-beta (receptor grade) into collagen gels embedded with fibroblasts, contraction being enhanced. Other growth factors tested, including transforming growth factor-alpha and epidermal growth factor, did not enhance the contraction of collagen gels containing embedded human and rodent fibroblasts. These results suggest that the activated form of TGF-beta released from gastric scirrhous carcinoma cells stimulates fibroblasts to contract the collagenous stroma of the stomach wall, which leads to the so-called "linitis plastica" stomach condition.

[In vivo measurements of electrical bio-impedance of breast tumors].

The electrical bio-impedance of 17 breast tumors including 12 breast cancers and 5 fibroadenomas, were measured in vivo with three-electrode method in the frequency range of 0 to 200 KHZ. The three-electrode consists of a coaxial needle electrode inserted into the tumor and a large reference electrode on upper abdominal wall. The tissue can be regarded electrically as a equivalent consisted of extracellular resistance (R1), intracellular resistance (R2), and electric capacitance of the cell membrane (C). These three parameters were calculated from the measured values of electrical bioimpedance. It was found that R1, and R2 of breast cancers were significantly higher than those of fibroadenomas (p less than 0.001), and that C of breast cancers was significantly lower than that of fibroadenomas (p less than 0.001). The measurement of the electrical impedance of breast tumor in vivo may be useful for the differential diagnosis of breast lesions.

[Estrogen receptors in primary breast neoplasms]. / Retseptory éstrogenov v pervichnoi opukholi u bol'nykh rakom molochnoi zhelezy.

Estrogen receptors were studied in 108 stage I and II breast cancer patients aged 28-83. The receptors were identified in 72.6% of cases, 55.5% of tumors being estrogen receptor-positive. Estrogen receptor level and frequency in tumor were found to depend upon patient's age and menstrual function. Mean estrogen receptor levels in patients with adrenal and involutive forms of cancer, which are the most sensitive to hormone therapy were 2-3 times those in ovarian and thyroid forms, the latter being the least sensitive to hormone treatment (ovariectomy + corticosteroids). Scirrhous tumors of the breast in elderly patients were mostly estrogen receptor-positive, this pointing to favorable prognosis in this age bracket.

Vitamin C and cancer: an overview.

The outcome of every cancer illness is determined to a significant extent by the inherent resistance of the individual patient to his or her disease. There is increasing recognition that resistance to cancer depends, to a certain extent, upon the availability of certain nutritional factors, of which ascorbic acid appears to be the most important. Ascorbic acid protects against the destructive effects of malignant invasiveness by stabilizing the ground substance and enhancing collagen encapsulation. It is also involved in the mechanisms of both cell-mediated and humoral immunity including the production of interferon, and other factors either known or thought to be involved collectively in host resistance to neoplasia. There is also some recent evidence suggesting that ascorbate exerts a selective cytotoxic effect against malignant cells. All these observations indicate that supplemental ascorbate should be of some therapeutic value in the treatment of cancer. Clinical trials conducted over the last decade are briefly reviewed, and the balance of evidence supports this contention. It is predicted that in the not-to-distant future, supplemental ascorbate will attain an established place in all comprehensive cancer treatment regimes.