Monoclonal antibodies (mAbs) against the extracellular domain of the epidermal growth factor receptor (EGFR) have been introduced for the treatment of metastatic colorectal cancer (mCRC). We have reported recently that increased copy number of the EGFR can predict response to anti-EGFR mAbs and that patients might be selected for treatment based on EGFR copy number. Here, we show that mutations activating the RAS/RAF signaling pathway are also predictive and prognostic indicators in mCRC patients, being inversely correlated with response to anti-EGFR mAbs. In cellular models of CRCs, activation of the RAS signaling pathway by introduction of an activated K-RAS allele (Gly¹²Val) impairs the therapeutic effect of anti-EGFR mAbs. In cancer cells carrying constitutively active RAS, the pharmacologic inhibition of the mitogen-activated protein kinase (MAPK) signaling cascade improves anti-EGFR treatment based on mAbs. These results have implications for the identification of patients who are likely to respond to anti-EGFR treatment. They also provide the rationale for combination therapies, targeted simultaneously to the EGFR and RAS/RAF/MAPK signaling pathways in CRC patients. [Cancer Res 2007;67(6):2643–8]

Metastases from different cancer types most often affect the lung parenchyma. Moreover, the lungs are among the most frequent sites of growth of metastatic masses of uncertain/unknown lineage of origin. Thus, with regards to pulmonary neoplastic parenchymal nodules, the critical issue is to determine if they are IN the lung or OF the lung. In this review, we highlight the clinical, instrumental and molecular features which characterize lung metastases, mainly focusing on recently advancing and emerging concepts regarding the metastatic niche, inflammation, angiogenesis, immune modulation and gene expression. A novel issue is related to the analysis of biomechanical forces which cooperate in the expansion of tumor masses in the lungs. We here aim to analyze the biological, genetic and pathological features of metastatic lesions to the lungs, here referred to as site of metastatic growth. This point should be a crucial part of the algorithm for a proper diagnostic and therapeutic approach in the era of personalized medicine.

The occurrence of oncogenic alleles can display striking tissue specificity. For example KRAS mutations are very frequent in pancreatic cancers but relatively rare in melanomas. The opposite is true for BRAF mutations. Somatic mutations in the gene encoding for the phosphatidylinositol 3-kinase (PI3KCA) catalytic subunit, PIK3CA, occur at high frequency in many solid cancers. We have examined whether PI3K oncogenic mutations (exons 9 and 20) might exhibit gender and/or tissue specificity. By examining large cohorts of breast and colorectal cancers affecting both men and women we found that the pattern of PIK3CA mutations is distinctive. In colorectal cancers, PIK3CA (but not KRAS, APC, or TP53) mutations display a gender bias occurring at higher frequencies in women. We also found that male breast cancers display PIK3CA mutations at an overall frequency similar to that observed in female breast tumors. In male breast cancers, however, PIK3CA mutations are found mainly in exon 20. We conclude that PI3KCA mutations affecting exons 9 and 20 display gender- and tissue-specific patterns, thus suggesting that the different amino acid changes could exert distinct functional effects on the oncogenic properties of this enzyme. Furthermore, we propose that sexual dimorphisms and tissue specific factors might directly or indirectly influence the occurrence of PI3KCA cancer alleles. Hum Mutat 29(2), 284–288, 2008.

Senescence, the molecular program that limits the finite proliferative potential of a cell, acts as an important barrier to protect the body from cancer. Techniques for measuring transcriptome changes and for modulating their expression suggest that it may be possible to dissect the transcriptional networks underlying complex cellular processes. HMF3A cells are conditionally immortalized human mammary fibroblasts that can be induced to undergo coordinated senescence. Here, we used these cells in conjunction with microarrays, RNA interference, and in silico promoter analysis to promote the dissection of the transcriptional networks responsible for regulating cellular senescence. We first identified changes in the transcriptome when HMF3A cells undergo senescence and then compared them with those observed upon replicative senescence in primary human mammary fibroblasts. In addition to DUSP1 and known p53 and E2F targets, a number of genes such as PHLDA1, NR4A3, and a novel splice variant of STAC were implicated in senescence. Their role in senescence was then analyzed by RNA silencing followed by microarray analysis. In silico promoter analysis of all differential genes predicted that nuclear factor-κB and C/EBP transcription factors are activated upon senescence, and we confirmed this by electrophoretic mobility shift assay. The results suggest a putative signaling network for cellular senescence.