Cecal Tumorigenesis in Aryl Hydrocarbon Receptor-Deficient Mice Depends on Cecum-Specific Mitogen-Activated Protein Kinase Pathway Activation and Inflammation.

The aryl hydrocarbon receptor (AhR) is a transcription factor known as a dioxin receptor. Recently, Ahr-/- mice were revealed to develop cecal tumors with inflammation and Wnt/ß-catenin pathway activation. However, whether ß-catenin degradation is AhR dependent remains unclear. To determine whether other signaling pathways function in Ahr-/- cecal tumorigenesis, we investigated histologic characteristics of the tumors and cytokine/chemokine production in tumors and Ahr-/- peritoneal macrophages. AhR expression was also assessed in human colorectal carcinomas. Of the 28 Ahr-/- mice, 10 developed cecal lesions by 50 weeks of age, an incidence significantly lower than previously reported. Cecal lesions of Ahr-/- mice developed from serrated hyperplasia to adenoma/dysplasia-like neoplasia with enhanced proliferation. Macrophage and neutrophil infiltration into the lesions was also observed early in serrated hyperplasia, although adjacent mucosa was devoid of inflammation. Il1b, Il6, Ccl2, and Cxcl5 were up-regulated at lesion sites, whereas only IL-6 production increased in Ahr-/- peritoneal macrophages after lipopolysaccharide + ATP stimulation. Neither Myc (alias c-myc) up-regulation nor ß-catenin nuclear translocation was observed, unlike previously reported. Interestingly, enhanced phosphorylation of extracellular signal-regulated kinase, Src, and epidermal growth factor receptor and Amphiregulin up-regulation at Ahr-/- lesion sites were detected. In human serrated lesions, however, AhR expression in epithelial cells was up-regulated despite morphologic similarity to Ahr-/- cecal lesions. Our results suggest novel mechanisms underlying Ahr-/- cecal tumorigenesis, depending primarily on cecum-specific mitogen-activated protein kinase pathway activation and inflammation.

ASC-associated inflammation promotes cecal tumorigenesis in aryl hydrocarbon receptor-deficient mice.

The aryl hydrocarbon receptor (AhR) plays a suppressive role in cecal carcinogenesis by CUL4B/AhR-mediated ubiquitylation and degradation of ß-catenin, which is activated by xenobiotics and natural ligands. AhR-deficient (AhR(-)(/-)) mice develop cecal tumors with severe inflammation. To elucidate whether the tumors develop autonomously in AhR(-/-) mice due to impaired ß-catenin degradation or in association with accelerated inflammation, we performed two kinds of experiments using germ-free (GF) AhR(-/-) mice and compound mutant mice lacking genes for AhR and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which plays an essential role in caspase-1 activation in inflammasomes. Both GF AhR(-/-) and AhR(-/-)•ASC(-/-) mice showed considerably reduced tumor development compared with that in AhR(-/-) mice albeit in a 'cancer-prone' state with aberrant ß-catenin accumulation. Blocking of the interleukin (IL)-1ß signaling pathway by treatment with a caspase-1 inhibitor, YVAD, reduced cecal tumorigenesis in AhR(-/-) mice. Signal transducers and activators of transcription 3 (STAT3) activation was detected in the cecal epithelium of the AhR(-/-) mice due to enhanced IL-6 production. An inhibitor of the STAT3 signaling pathway, AG490 suppressed the tumor formation. ASC-mediated inflammation was also found to play a critical role in tumor development in Apc(Min/+) mice, a mouse model of familial adenomatous polyposis. Collectively, these results revealed an important role of the bacteria-triggered or ASC-mediated inflammation signaling pathway in the intestinal tumorigenesis of mice and suggest a possible chemical therapeutic intervention, including AhR ligands and inhibitors of the inflammation pathway.

Gastrointestinal glomus tumors: a clinicopathologic, immunohistochemical, and molecular genetic study of 32 cases.

Glomus tumors usually occur in the peripheral soft tissues, but similar tumors have also been reported in the stomach and occasionally in the intestines. However, the relationship of these tumors to peripheral glomus tumors and gastrointestinal stromal tumors has not been fully clarified because previous series of gastrointestinal glomus tumors predate availability of immunohistochemistry. This clinicopathologic study examined 32 gastrointestinal glomus tumors. All but one of the tumors were located in the stomach and the remaining tumor was from the cecum. The tumors occurred with a strong female predominance (23 females and 9 males) and a median age of 55 years (range 19-90 years). The gastric tumors typically presented with gastrointestinal bleeding or ulcer-like symptoms, and 14 tumors had mucosal ulceration. Five tumors were incidental findings. The tumor sizes varied from 1.1 to 7 cm (median 2 cm), and most were located in the antrum. Histologically, the tumors typically had a solid pattern of sharply demarcated, round glomus cells with prominent, mildly dilated pericytoma-like vessels. Vascular invasion and focal atypia were relatively common (seen in 11 and 13 cases, respectively), and low mitotic activity (1-4 per 50 high power fields), was seen in 10 cases. Immunohistochemically, all tumors were positive for alpha-smooth muscle actin and calponin, and nearly all had a net-like pericellular laminin and collagen type IV positivity. All tumors were negative for desmin and S-100 protein. Three tumors had focal synaptophysin positivity, but none was positive for chromogranin. All tumors lacked KIT expression and the GIST-specific mutations in the c-kit gene. Follow-up revealed one patient death of metastatic disease to liver at 50 months; this tumor had 1 mitosis per 50 high power fields, but had spindle cell foci, mild atypia, and vascular invasion. Thirteen patients were well and alive after long-term follow-up. Gastrointestinal glomus tumors occur almost exclusively in the stomach, and they have a good overall prognosis, but a small, unpredictable potential for malignant behavior exists. These tumors are phenotypically similar to peripheral glomus tumors and differ from epithelioid GISTs.

Cytokeratin staining for primary and metastatic colorectal cancer.

Determining the site of origin of metastatic adenocarcinoma lesions has obvious therapeutic and prognostic implications. Immunostaining for cytokeratin subtypes 7 and 20 is increasingly used to evaluate metastatic colorectal cancer lesions. We present the case of a patient with a history of colorectal cancer who subsequently developed an isolated metastatic lesion in the lung. As illustrated by our case, staining for cytokeratin subtypes can be helpful in determining the site of origin of metastatic lesions.

A neoadjuvant clinical trial in colorectal cancer patients of the human anti-idiotypic antibody 105AD7, which mimics CD55.

Thirty-five patients received 105AD7 human anti-idiotype vaccination prior to surgery for colorectal carcinoma. Patients were immunized before and also received one to two immunizations after surgical resection of their colorectal cancer. The vaccine was well tolerated with no associated toxicity. Lymphocytic infiltration within the resected tumors was quantified by immunohistochemistry and image analysis. Enhanced infiltration of helper T cells (CD4) and natural killer (NK) cells (CD56) were observed in the tumors from immunized patients when compared with tumors from stage, grade, site, age, and sex matched unimmunized patients. NK activity was increased in the blood, peaking 7-10 days post immunization and then dropping rapidly and correlating with NK extravasation within the tumor. Comparison of the amino acid sequences of 105AD7 anti-idiotype and the antigen it mimics, CD55, has predicted that patients with HLA-DR1, HLA-DR3, and HLA-DR7 haplotypes should show helper T cell responses following 105AD7 vaccination. Eighty-three percent of patients expressing these haplotypes responded to 105AD7, whereas 88% of patients who failed to express these haplotypes were nonresponders. With a median follow-up of 4 years (range, 2.5-6 years) 65% of patients remained disease free. This trial shows that 105AD7 stimulates antitumor inflammatory responses allowing extravasation within tumor deposits of both helper T cells and NK cells. This represents a way of evaluating immune responses in patients both within the blood and at the tumor site. The study confirms that immunization with a human anti-idiotypic antibody results in immune responses in 83% of patients with a permissive haplotype.

Anaplastic solitary extramedullary plasmacytoma of the cecum. Report of a case confirmed by immunoperoxidase staining.

Solitary extramedullary plasma cell tumors, although uncommon, have been reported with increasing frequency over the last few years. Approximately 5 to 10 percent of the tumors arise in the gastrointestinal tract. This report demonstrates that a solitary anaplastic cecal extramedullary plasmacytoma can mimic a polypoid carcinoma, both grossly and, to an extent, microscopically. Immunoperoxidase stains for cytoplasmic immunoglobulin proved useful in establishing the correct diagnosis.

Mixed crypt cell carcinoma. A clinicopathological study of the so-called 'goblet cell carcinoid'.

The clinicopathological features of six appendix and five bowel tumours with features of the so-called 'goblet cell carcinoid' are described. By light microscopy, these tumours were composed predominantly of mucous cells, together with variable proportions of endocrine and Paneth cells. Immunohistochemical and ultrastructural study confirmed this impression and no amphicrine cells were seen. The clinical course of all cases arising in the bowel, and three out of six appendix tumours was characterised by an aggressive behaviour with the development of widespread lymphatic and often intraperitoneal metastasis, but liver metastasis occurred in only one instance. We conclude, both from this study and from a review of the literature, that the 'mixed crypt cell carcinoma' forms a distinct clinicopathological entity justifying separate classification from adenocarcinoma and carcinoid tumour.

Genetic control of the resistance to spontaneous immunocytoma (plasmacytoma-IR tumour) development in LOU/C rats.

Immunocytomas (immunoglobulin secreting tumours) appear with a highly spontaneous incidence in animals of the inbred LOU/C strain but never in those of the inbred OKA strain. Congenic rats with LOU/C genetic background, having either the heavy or the kappa light immunoglobulin chain loci from the OKA strain, have an immunocytoma incidence similar to that of the LOU/C strain. The congenic strain, having the major histocompatibility complex of the OKA strain on the LOU/C background, showed no immunocytoma incidence. These results indicate that the MHC locus of the rat, or a gene closely linked to it, determines resistance to immunocytoma development. Specific chromosomal translocation associated with Ig gene chromosome and c-myc play a major role in the origin of the rat IR tumours. These experiments show that the resistance of the OKA strain to the appearance of IR tumours is not correlated with special properties of Ig heavy and kappa gene segments.

The local immune response to large bowel tumors.

Methods are described for the purification on isokinetic gradients of isolated large bowel lamina propria lymphocytes (LPL) and large bowel adenocarcinoma-infiltrating lymphocytes (TIL). The in vitro cytotoxic and proliferative responses of these lymphocytes and of peripheral blood lymphocytes from tumor patients were assayed. Neither K cell nor NK cell cytotoxic activity was detected in LPL and TIL, although both types of lytic response were present in PBL. Lectin-induced cytotoxicity was mediated by LPL and TIL populations, but their responses in this assay were reduced comparable to that of PBL. Although TIL comprised equivalent T cell proportions to PBL, the proliferative response of TIL T cells was comparatively lower. LPL and TIL populations, but their responses in this assay were reduced comparable to that of PBL. Although TIL comprised equivalent T cell proportions to PBL, the proliferative response of TIL T cells was comparatively lower. Co-culture experiments and attempts to induce suppressor cells with concanavalin A suggested that the reduced proliferative response of T cells infiltrating these tumors was not due to the action of suppressor lymphocytes.

Coexisting primary malignant lymphoma and adenocarcinoma of the large intestine in an IgA-deficient boy.

This is a case report of an IgA-deficient adolescent male (14 years old) presenting with coexisting adenocarcinoma and adenomatous polyp of the rectosigmoid, and a primary lymphoma of the cecum (large-cell, histiocytic type). A 14-year-old sister of the patient had died of gastric carcinoma. Her serum immunoglobulins were not measured. The literature regarding the coexisting primary malignant lymphoma and adenocarcinoma of the colon, as well as neoplasia associated with IgA deficiency, is reviewed and pertinent literature discussed.

Plasma carcinoembryonic antigen concentrations and immunohistochemical patterns of epithelial marker antigens in patients with large bowel carcinoma.

Carcinoembryonic antigen (CEA), secretory component (SC), and epithelial IgA were traced by paired immunofluorescence staining in 102 large bowel carcinomas from 99 patients. The immunohistochemical results were evaluated semiquantitatively in relation to histological tumour grade, clinicopathological stage, and preoperative plasma CEA concentration. CEA expression was significantly increased (p less than 0.05) in the following order: histologically normal colon mucosa, transitional mucosa adjacent to tumours, neoplastic epithelium; the reverse was true for the expression of SC and epithelial IgA (p less than 0.01). CEA was significantly more abundant in the moderately and poorly differentiated tumors than in the well differentiated ones (p less than 0.05), whereas the latter showed better expression of SC (p less than 0.05) and epithelial IgA (p approximately 0.06). In the transitional mucosa, CEA staining tended to be inversely related to histological tumour grade, whereas SC and epithelial IgA were significantly better seen in this zone when the adjacent tumour was well differentiated than when it was moderately or poorly differentiated (p less than 0.01). Furthermore, the expression of SC and epithelial IgA in the transitional mucosa decreased with increasing invasiveness of the tumours, whereas the opposite relation was indicated for CEA expression. Plasma CEA concentrations were not clearly correlated with histological levels than the localised well differentiated tumours tended to be associated with lower levels than the localised moderately differentiated ones (p approximately 0.06). Moreover, the latter variety was associated with lower plasma CEA concentrations than disseminated tumours of comparable differentiation (p less than 0.01).

Rat ileocecal immunocytoma. An ultrastructural study with special attention to the presence of viral particles.

Fifteen spontaneous immunocytomas originating in the ileocecal lymph nodes of Lou/C/Wsl rats were studied by means of electron microscopy. The histology was characteristic, the tumor being formed by an accumulation of large, rounded cells with slightly eccentric ovoid nuclei, large nucleoli, and finely condensed chromatin along the nuclear walls; the cytoplasma was rich in polyribosomes. The appearance of the rough endoplasmic reticulum was apparently the same whether or not the tumor was secretory. Its development varied from one cell to another, and in only a small proportion of cells did it attain any considerable volume. In all the tumors examined, we noted the presence of intracisternal A-particles. In its morphology, the rat immunocytoma resembled the plasmacytomas induced in mice, and it also resembled certain human tumors such as Burkitt's lymphoma.

Decrease in the incidence of malignant ileo-caecal immunocytoma in LOU/C rats after surgical removal of the ileo-caecal lymph nodes.

Malignant ileo-caecal immunocytomata, which secrete immunoglobulin, frequently arise spontaneously in LOU/C/Wsl rats. The tumors are confined to the ileo-caecal region and could originate either in the wall of the caecum or in the ileo-caecal lymph nodes. After excision of the ileo-caecal lymph nodes, the incidence of the type of tumor was found to be reduced significantly. The results strongly suggest that the first cells to undergo malignant transformation are located in the ileo-caecal nodes.

Solitary cecal plasmacytoma: electron microscopic, immunologic, and cytochemical studies.

A case of solitary cecal plasmacytoma is described with strong evidence of IgGk paraprotein production demonstrated by immunofluorescence and electromicroscopy. This is the ninth case of colonic plasmacytoma reported in the English literature and the first to show positive immunofluorescence.