Prognostic Impact of LGR5, Prox1, and Notch1 Biomarkers in Stage II to III Colon Cancer

Abstract

The potentiation and activation of Wnt signaling pathways are now assumed to mediate the self-renewal and proliferation of colon cancer stem cells that are responsible for therapeutic resistance, tumor relapse, and metastasis. We aimed to evaluate LGR5, Prox1, and Notch1 immunohistochemical expression in stage II to III colon cancer. Their predictive role of tumor relapse, overall survival, and disease-free survival was statistically analyzed. Our results revealed that high LGR5 expression was identified in 56.7% of the patients, LGR5 expression was significantly associated with left-sided tumors (P < 0.001). Moreover, its expression was significantly associated with the unfavorable tumor characteristics including high grade, deep invasion (pT), lymph node metastasis, and advanced tumor stage (P < 0.001 for each). High Prox1 expression was observed in 65% of the cases, and its expression was significantly associated with tumor grade, lymph node metastasis, and the advanced tumor stage (P = 0.004, 0.009, 0.016, respectively). Positive Notch1 expression was identified in 35% of patients, and it was inversely associated with high grade lymph node metastasis, deep invasion (pT), and advanced tumor stage (P < 0.001 for each). During the follow-up period, the tumor relapse was significantly associated with high LGR5, high Prox1, and negative Notch1 expression. Shorter overall survival and disease-free survival were significantly associated with high LGR5, high Prox1, and negative Notch1 expression. High LGR5, high Prox1, and negative Notch1 expression are unfavorable prognostic factors in colon cancer. Prox1 is a crucial regulator of Notch-independent LGR5+ stem cells that is mostly responsible for relapse and therapeutic resistance in stage II to III colon cancer.

The Role of PROX1 in Neoplasia: A Key Player Often Overlooked

“…Moreover, patients with higher PROX1 expression had an elevated risk of death and reduced OS rates after adjustments were made for age, sex, and tumor size [ 44 ]. Similar results are published by Abdelrahman et al in a cohort of stage-II/III colon cancer cases [ 45 ].…”

Ten-Year Recurrence Outcomes in Early Stage and Early Onset Colon Cancer and the Expression Profiles of MicroRNAs and Cancer Stem Cell Markers in These Tumors

“…11,12 In a recent study, LGR5+ stem cells were reported to be responsible for recurrence and therapeutic resistance in Stage II-III colon cancer. 13 In our study, CD133, SOX2 and LGR5 were used to determine CSC status. High expression of at least two of them was accepted as a criterion for CSCpositive tumors.…”

Tissue-specific cancer stem/progenitor cells: Therapeutic implications

“…However, the combination of multiple markers allows more accurate detection of CSCs which was proven when LGR5, CD44 and EpCAM resulted in more potent CSCs properties as compared to each marker alone[ 56 ]. Other markers are also attributed to CCSCs such as CD59[ 69 ], Prox1 a regulator of Notch-independent LGR5 + SCs[ 70 , 71 ], CD24[ 4 , 64 ], CD166[ 72 ], and ABCB5 (ATP binding cassette super-family B member 5)[ 73 ].…”