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Extending the Reach of IL13 Cytotoxin in Anticancer Therapy

  1. Top of page
  2. Extending the Reach of IL13 Cytotoxin in Anticancer Therapy
  3. Mucin-Depleted Foci: Novel Markers of Colon Carcinogenesis
  4. Survivin, an Inhibitor of Apoptosis, Is a Novel Marker for Bladder Transitional Cell Carcinoma

Saito et al., 1–8

IL13 cytotoxin, a fusion protein composed of IL13 and Pseudomonas exotoxin A, is a potent new anticancer drug that selectively targets tumor cells overexpressing the α2 chain of the IL13 receptor. The α2 chain is a decoy receptor that binds and internalizes IL13 without induction of the signaling cascade. It is overexpressed in several types of human cancers, including renal cell carcinoma, gliomas, AIDS-associated Kaposi sarcoma, head-and-neck cancer and some forms of ovarian cancer.

However, the majority of human malignancies do not express high levels of the α2 chain of the IL13 receptor. To extend the cytotoxic reach of the drug, Saito and colleagues overexpressed the α2 chain in formerly negative tumor cells using adenoviral vectors. More than 80% of A549 cells (a human lung cancer cell line) and more than 70% of HOS cells (a human osteosarcoma cell line) expressed the receptor after infection and became susceptible to killing by IL13 cytotoxin.

A dramatic reduction in tumor growth was observed when A549 cells were subcutaneously injected into nude mice. Established tumors were treated once with an intratumoral injection of IL13Rα2-expressing adenoviral vectors and immediately regressed, and growth was halted under daily intratumoral injections of IL13 cytotoxin. No histologic changes or side effects in nontargeted organs were observed. Interestingly, mice treated only with IL13Rα2-expressing vectors, but not control adenoviral vectors showed infiltration of inflammatory cells into the tumor tissue, indicating the induction of an antitumoral immune response by the decoy receptor. While the study proves the efficacy and safety of the system in mice, the authors caution that a highly specific gene delivery system will be needed to transfer the system into patients.1

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Illustration 1. Altered β-catenin localization in MDF (white arrows) with cytoplasmic and nuclear staining in contrast to membraneous staining in a normal crypt (black arrow).

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Mucin-Depleted Foci: Novel Markers of Colon Carcinogenesis

  1. Top of page
  2. Extending the Reach of IL13 Cytotoxin in Anticancer Therapy
  3. Mucin-Depleted Foci: Novel Markers of Colon Carcinogenesis
  4. Survivin, an Inhibitor of Apoptosis, Is a Novel Marker for Bladder Transitional Cell Carcinoma

Femia et al., 9–15

Mucin-depleted foci (MDF) are colon lesions characterized by reduced mucous production previously identified in rats treated with azoxymethane. These lesions were found along the mucosal surface and showed histologic signs of dysplasia. In this issue of IJC, Femia and colleagues provide evidence that MDF represent bona fide preneoplastic lesions. They found that the number and size of MDF increased over time in F344 rats treated with 1,2-dimethylhydrazine. Numbers decreased when tumors appeared, suggesting that MDFs were transformed into more advanced lesions. Accordingly, MDF and tumors showed overlapping localizations with a high prevalence in distal parts of the colon.

The authors also analyzed the subcellular localization of β-catenin. Abnormal activation of the Wnt signaling pathway is a marker of colon carcinogenesis. They report a striking reduction of membrane-localized β-catenin and a proportional increase in cytoplasmic and nuclear localization of the transcription factor in MDF and tumors. In some samples, this result was supported by mutations in the β-catenin gene (Ctnnb1), mutating serine residues important for phosphorylation and degradation of β-catenin in the cytoplasm. The authors speculate that constitutive activation of the Wnt pathway in MDF may lead to increased cell proliferation and uncontrolled tumor growth. Alternatively, it might cause a depletion of mucins, since suppression of Wnt signaling can upregulate MUC2, the most abundantly secreted apomucin in the colon.

Survivin, an Inhibitor of Apoptosis, Is a Novel Marker for Bladder Transitional Cell Carcinoma

  1. Top of page
  2. Extending the Reach of IL13 Cytotoxin in Anticancer Therapy
  3. Mucin-Depleted Foci: Novel Markers of Colon Carcinogenesis
  4. Survivin, an Inhibitor of Apoptosis, Is a Novel Marker for Bladder Transitional Cell Carcinoma

Weikert et al., 100–104

Inhibition of apoptosis plays a significant role in tumorigenesis in a number of tumors. It is generally accepted that elevated expression of regulatory factors of antiapoptosis promotes aggressive tumor behavior and resistance to therapy. Survivin is an inhibitor of apoptosis that shows selective overexpression in common human malignancies and is barely detectable in normal differentiated adult tissues. Survivin is expressed in cancer cells at the G2/M phase of the cell cycle and suppresses the induction of apoptosis at that point of the cell cycle by inhibiting the activity of caspases.

Weikert and colleagues have measured survivin mRNA levels using a sensitive real-time PCR assay and assessed its potential as a diagnostic and prognostic factor in bladder cancer. They studied 53 patients with bladder transitional cell carcinoma (TCC) and compared them to a group of normal individuals. They report that survivin levels were detected in tumor tissues but not in normal urothelium and that survivin mRNA levels correlated positively with progressing pathologic stage and grade categories. Urinary survivin measurement detected TCC with higher sensitivity and equal specificity when compared to cytology. These observations indicate that survivin is a highly specific biomarker for TCC detection.