The regulation of cell growth and survival can be subverted by a variety of genetic defects that alter transcriptional programs normally responsible for controlling cell number. High throughput analysis of these gene expression patterns should ultimately lead to the identification of minimal expression profiles that will serve as common denominators in assigning a cancer to a given category. In the course of defining the common denominators, though, we should not be too surprised to find that cancers within a single category may nevertheless exhibit seemingly disparate genetic defects. The wnt pathway has already provided an outstanding example of this. We now know of three regulatory genes in this pathway that are mutated in primary human cancers and several others that promote experimental cancers in rodents (Fig. 1). In all of these cases the common denominator is the activation of gene transcription by -catenin. The resulting gene expression profile should provide us with a signature common to those cancers carrying defects in the wnt pathway. In this review, the wnt pathway will be covered from the perspective of cancer, with emphasis placed on molecular defects known to promote neoplastic transformation in humans and in animal models.

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Wnt signaling and cancer

Suppression of Intestinal Polyposis in ApcΔ716 Knockout Mice by Inhibition of Cyclooxygenase 2 (COX-2)

Mutations of the genes encoding APC or beta-catenin in colon carcinoma induce the constitutive formation of nuclear beta-catenin/Tcf-4 complexes, resulting in activated transcription of Tcf target genes. To study the physiological role of Tcf-4 (which is encoded by the Tcf7/2 gene), we disrupted Tcf7/2 by homologous recombination. Tcf7/2-/- mice die shortly after birth. A single histopathological abnormality was observed. An apparently normal transition of intestinal endoderm into epithelium occurred at approximately embryonic day (E) 14.5. However, no proliferative compartments were maintained in the prospective crypt regions between the villi. As a consequence, the neonatal epithelium was composed entirely of differentiated, non-dividing villus cells. We conclude that the genetic program controlled by Tcf-4 maintains the crypt stem cells of the small intestine. The constitutive activity of Tcf-4 in APC-deficient human epithelial cells may contribute to their malignant transformation by maintaining stem-cell characteristics.

Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4.

https://pure.knaw.nl/ws/files/7023847/S0092_8674_00_00122_7_1_.pdf

Linking Colorectal Cancer to Wnt Signaling

Caught up in a Wnt storm: Wnt signaling in cancer.

Mutations in the APC (adenomatous polyposis coli) gene appear to be responsible for not only familial adenomatous polyposis but also many sporadic cases of gastrointestinal cancers. Using homologous recombination in mouse embryonic stem cells, we constructed mice that contained a mutant gene encoding a product truncated at a 716 (Apc delta 716). Mendelian transmission of the gene caused most homozygous mice to die in utero before day 8 of gestation. The heterozygotes developed multiple polyps throughout the intestinal tract, mostly in the small intestine. The earliest polyps arose multifocally during the third week after birth, and new polyps continued to appear thereafter. Surprisingly, every nascent polyp consisted of a microadenoma covered with a layer of the normal villous epithelium. These microadenomas originated from single crypts by forming abnormal outpockets into the inner (lacteal) side of the neighboring villi. We carefully dissected such microadenomas from nascent polyps by peeling off the normal epithelium and determined their genotype by PCR: all microadenomas had already lost the wild-type Apc allele, whereas the mutant allele remained unchanged. These results indicate that loss of heterozygosity followed by formation of intravillous microadenomas is responsible for polyposis in Apc delta 716 intestinal mucosa. It is therefore unlikely that the truncated product interacts directly with the wild-type protein and causes the microadenomas by a dominant negative mechanism.

https://www.pnas.org/content/pnas/92/10/4482.full.pdf

Loss of Apc heterozygosity and abnormal tissue building in nascent intestinal polyps in mice carrying a truncated Apc gene.

Summary Lesions of chickens inoculated with two highly pathogenic avian influenza virus strains, A/turkey/England/50–92/91 (H5N1) and A/chicken/Victoria/1/85 (H7N7) were examined histologically and immunohistochemically. Birds of both treatment groups died within 5 days post‐inoculation. The most significant lesions induced by these two viruses consisted of swelling of the microvascular endothelium, systemic congestion, multifocal haemorrhages, perivascular mononuclear cell infiltration, and thrombosis associated with viral antigen in the vascular endothelium and/or perivascular parenchymatous cells. Viral antigen in the cardiac myocytes was consistently detected in all birds. In addition, severe pulmonary congestion and oedema was found in A/turkey/England/50–92/91 virus‐inoculated birds that died within 1 day post‐inoculation. The other chickens of both groups showed necrotic and inflammatory changes associated with viral antigen in various organs and tissues. These findings suggested that cardiovascula...

https://www.tandfonline.com/doi/pdf/10.1080/03079459608419142

Pathological studies of chickens experimentally infected with two highly pathogenic avian influenza viruses

One-day-old chicks, inoculated intramuscularly with the MSB1-TK5803 strain of chicken anaemia agent (CAA), showed a decrease of haematocrit value and inhibition of body weight gain, particularly between days 12 and 20 post inoculation (pi). Macroscopically, yellowish bone marrow, atrophy of the thymus and bursa of Fabricius, enlargement and discoloration of liver were observed in most chicks at the peak of infection. Histologically, the lesions appeared first in bone marrow and thymus on day 6 pi, and then in the bursa, spleen and liver. Swelling and intranuclear inclusion bodies in the haematopoietic precursor cells, thymocytes and reticular cells of the thymus were considered to be characteristic lesions. Hypoplasia or aplasia of bone marrow, depletion of lymphocytes in the lymphoid organs and swelling of hepatocytes occurred during the anaemic phase. Repopulation of the haematopoietic cells and lymphocytes occurred between days 16 and 24 pi, and most tissues of the surviving chicks recovered by day 32 pi.

https://www.tandfonline.com/doi/pdf/10.1080/03079458908418581

Histopathology of chicks inoculated with chicken anaemia agent (MSB1-TK5803 strain).

Two-day-old specific-pathogen-free chicks were inoculated intranasally with the MA-87 strain of infectious bronchitis virus, and trachea and kidney lesions studied histologically and immunohistochemically. Lesions and viral antigen were first detected in the trachea; severe damage was then observed in the kidney. Viral antigen appeared prior to the development of renal lesions and was detected in the cytoplasm of epithelial cells by 4 days post-inoculation (p.i.). The epithelial cells of the collecting ducts, collecting tubules and distal convoluted tubules were first affected, followed by involvement of Henle's loops, whereas the proximal convoluted tubules were only minimally affected. Antigen-positive cells of ducts and tubules were degenerated and desquamated. The severe epithelial cell damage resulted in infiltration of heterophils and macrophages in the interstitium, ducts and tubules. The detection of viral antigen was consistent with the distribution of histological lesions at 6 to 8 days p.i. At a later stage, antigen-positive cells disappeared and repair of epithelial cells was seen, accompanied by interstitial lymphoplasmacytic infiltration and lymphoid nodular formation.

Chitoshi Itakura

Papers

Loss of Apc heterozygosity and abnormal tissue building in nascent intestinal polyps in mice carrying a truncated Apc gene.

Pathological studies of chickens experimentally infected with two highly pathogenic avian influenza viruses

Histopathology of chicks inoculated with chicken anaemia agent (MSB1-TK5803 strain).

Histopathology and immunohistochemistry of renal lesions due to infectious bronchitis virus in chicks.

Hepatic lesions in young rabbits experimentally infected with rabbit haemorrhagic disease virus.