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We have used human specimens and antibodies to pERK1/2 to detect early developmentof colon cancer, using indirect immunocytochemistry. Two distinct sites were stained;one at the tip of the colon villi and the other in the stromal tissue, associatedwith the colon tissue. These foci represent early stages of colon cancer initiation,as established by enhanced KRAS, and lack of p53 staining. It should be noted,however, that the enhanced KRAS coincides with the initiation of tumor growthrevealed by pERK1/2 only in the tip of the colon villi but not in the stromalinitiation site of the colon tumors. Interestingly, foci of pERK1/2 staining werealso detected within 50% of stromal tissue and tips of colon villi, that wereclassified as normal tissues, distal from the malignant one according to generalmorphology. The staining of pERK1/2 at the stromal foci of this apparently non-malignanttissue appeared as aggregates at the perinuclear region, while at the colon epithelium,it appeared at the cell nuclei. At low-grade of colon cancer, that was still freeof induced mutated p53, staining of pERK1/2 was prominent at the cell nuclei bothat the stroma tissue and the tip of the colon villi. In intermediate stage, thatexhibited a significant p53 staining, only a fraction of p53-free tumor cellswas labeled with pERK1/2 antibody, while in high-grade tumors, all cells of tumorswere labeled with antibodies to p53, but not with pERK1/2. We also found thatthe cytoplasm of low-grade tumors was positive for epiregulin, while this labelingdecreased in high-grade tumors. Interestingly, we found that the tumors initiatingfrom the stroma demonstrated poor structural differentiation, while the tumorsinitiating from the epithelial cells of the colon demonstrated high structuraldifferentiation. It is concluded that pERK1/2 is a sensitive early marker of coloncancer, which disappears at later stages of cancer development. Moreover, pERK1/2staining can distinguish between tumor cells originated from the tip of the colonvilli and those originated in the stroma, associated with the colon tissue, andthus can assist in selecting the appropriate therapy.

international journal of oncology

Two initiation sites of early detection of colon cancer, revealed by localization of pERK1/2 in the nuclei or in aggregates at the perinuclear region of tumor cells