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View the Table of Contents for the April 2007 issue of Molecular Cancer Therapeutics
Page 1186
The host stromal response to an invasive epithelial carcinoma is frequently called a desmoplastic reaction (DR) and is a universal feature of pancreatic ductal adenocarcinoma (PDA). This DR is characterized by a complex interplay between the normal host epithelial cells, invading tumor cells, stromal fibroblasts, inflammatory cells, proliferating endothelial cells, an altered extracellular matrix (ECM), and growth factors activating oncogenic signaling pathways by autocrine and paracrine mechanisms. Hence, the tumor microenvironment is a dynamic process promoting tumor growth and invasion through mechanisms likely to include anoikis resistance, genomic instability, and drug resistance. Mahadevan and von Hoff review the current understanding of the mechanisms that potentially drive the DR in PDA and future possibilities for therapeutic targeting of this critical process.
Page 1212
While astrocytic brain tumors do not metastasize systemically, during tumorigenesis glioma cells adopt an invasive phenotype that is poorly targeted by conventional therapies, hence glioma patients die of recurrence from the locally invasive tumor population. Demuth et al. have described discovery and validation of the novel target MKK3 in glioma. Survival analysis revealed that MKK3 was a predictor of short term survival which together with up-regulation of MKK3 in invasive glioma cells points towards its important role in glioma biology. The synthetic lethal combination of p38 inhibitor and temozolomide underscores its therapeutic potential.
Page 1223
In non-small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) mutational analysis is an excellent predictor of responsiveness to treatment with tyrosine kinase inhibitors (TKIs) such as gefitinib. Daniele et al. sought to determine the optimal scoring method for FISH or chromogenic (CISH) in situ hybridization assays when analysing small NSCLC samples in order to predict response. When only endoscopic biopsies or cytological specimens are available, the authors concluded that FISH/CISH for EGFR and HER2 was the test of choice for selecting patients for treatment with gefitinib and to consider as negative predictive factor the absence of EGFR/HER2 gene gain.
Page 1239
Gemcitabine is a nucleoside analogue that is incorporated into replicating DNA, resulting in partial chain termination and stalling of replication forks. The histone variant, H2AX, is phosphorylated on Ser139 (γ-H2AX) and forms nuclear foci at sites of DNA damage. Ewald et al. demonstrated cellular responses to the stalling of DNA replication forks by nucleoside analogues, including activation of the S-phase DNA damage checkpoint. This was associated with the phosphorylation of the histone variant, H2AX specifically in S-phase cells. Furthermore, as H2AX phosphorylation is diagnostic for DNA damage, the authors’ finding of a 10-fold increase in H2AX phosphorylation within 3 hours of checkpoint abrogation with a further decrease in clonogenic survival, demonstrated a likely basis for cell death in S-phase arrested cells, and provided a rationale for the design of combination chemotherapies.
Page 1249
Diallyl trisulfide (DATS), a highly promising anticancer constituent of processed garlic, inhibits growth of cancer cells by blocking cell cycle progression but the mechanism is not fully understood. Herman-Antosiewicz et al. provided experimental evidence to indicate activation of a novel DATS-mediated and ataxia-telangiectasia mutated and Rad3 related (ATR)/checkpoint kinase 1 (Chk1)-dependent pro-metaphase checkpoint in cancer cells that is strikingly different from the recently described ionizing radiation-induced mitotic exit checkpoint, which is Chk1-dependent but leads to accumulation of telophase cells.