Prognostic significance of p16, p21, and Ki67 expression at the invasive front of colorectal cancers

Abstract

Cancer cells at the invasive front are believed to be responsible for invasion/metastasis. This has led to examining various morphological features and protein expressions at the invasive front. However, accurate assessment of the pathological section requires long‐time training, and inter‐observer disagreement is problematic. Immunohistochemistry and digital imaging analysis may mitigate these problems; however, the choice of which proteins to stain and the best analysis method remains controversial. We used the “go‐or‐grow” hypothesis to select markers with the greatest prognostic relevance. Importantly, nonproliferating cells can migrate. We used Ki67 as a proliferation marker, with p16 and p21 designating nonproliferating cells. We established a semi‐automated quantification workflow to study protein expression in serial pathological sections. A total of 51 patients with completely resected colorectal cancer (stages I–IV) were analyzed, and 44 patients were followed up. Patients with cancer cells with p16‐high/p21‐low or p21‐low/Ki67‐low at the deepest invasive front demonstrated a significantly worse prognosis than those who did not display these characteristics. These results suggest that the nonproliferating cancer cells at the invasion front possess invasion/metastatic property with heterogeneity of senescence.

p16 Expression in Multinucleated Stromal Cells of Fibroepithelial Polyps of the Anus (FEPA): A Comprehensive Review and Our Experience

“…It has been shown to be highly related to the onset of numerous malignancies, such as bladder cancer, lung cancer, brain cancer, and esophageal cancer. They have been associated with the onset, progression, and prognosis of aberrant methylation of the promoters of the p16 gene [28]. Similarly, a study by Veganzones-de-Castro et al raised the possibility that the clinicopathologic characteristics of CRC may be significantly correlated with promoter hypermethylation of the p16 gene [29].…”

Differences in Clinicopathological Features, P16Ink4a and P57KIP2 Immunohistochemical Expressions, and Survival Between Colorectal Carcinoma in Rectosigmoid and Other Colonic Locations

“…Moreover, P16 expression has been linked to human papillomavirus (HPV) infection in CRC [ 16 ]. P16's precise association with clinicopathological data and survival probability in CRC is still questionable [ 15 , 17 ].…”