New Horizons in Metastatic Colorectal Cancer: Prognostic Role of CD44 Expression

Abstract

Background: The transmembrane glycoprotein CD44, the major hyaluronan (HA) receptor, has been proven to regulate cell growth, survival, differentiation, and migration. It is therefore widely considered to be involved in carcinogenesis. Its role as a new therapeutic target in solid tumors is under evaluation in clinical trials. The prognostic value remains controversial. Here, we aimed to investigate the correlation between CD44 expression and the clinicopathological features and survival in metastatic colorectal cancer (mCRC) patients. Methods: Data from 65 mCRC patients of the Medical Oncology Unit, University Hospital and University of Cagliari were retrospectively collected from 2008 to 2021. Immunohistochemical analysis was performed at the Pathology Division, University Hospital of Cagliari on 3 μm thick sections obtained from paraffin blocks. The intensity of immunohistochemical staining was subclassified into four groups: score 0 if negative or weak membrane staining in less than 10% of tumor cells; score 1+ if weak membrane staining in at least 10% of tumor cells or moderate membrane staining in less than 10% of tumor cells; score 2+ if moderate membrane staining in at least 10% of tumor cells or intensive membrane staining in less than 10% of tumor cells; score 3+ if intense membrane staining in at least 10% of tumor cells. Based on this score, we distinguished patients into low CD44 expression (score 0, 1+, 2+) and high CD44 expression (score 3+). Statistical analysis was performed with MedCalc (survival distribution: Kaplan–Meier; survival comparison: log-rank test; association between categorical variables: Fisher’s exact test). Results: Patients’ median age was 66 years (range 49–85). Regarding CD44 expression, score was 0 in 18 patients, 1+ in 15 patients, 2+ in 18 patients, and 3+ in 14 patients. Median overall survival (mOS) was 28.1 months (95%CI: 21.3–101). CD44 overexpression (3+) was correlated with poor prognosis (p = 0.0011; HR = 0.2), with a mOS of 14.5 months (95%CI 11.7 to 35.9) versus 30.7 months (95%CI 27.8 to 101) in lower CD44 expression. Higher CD44 expression was associated with clinically poor prognostic features: age ≥ 70 years (p = 0.0166); inoperable disease (p = 0.0008); stage IV at diagnosis (p = 0.0241); BRAF mutated (p = 0.0111), high-grade tumor (p = 0.0084). Conclusions: CD44 markedly correlated with aggressive tumor behavior and contributed to the earlier progression of disease, thus suggesting its role as a novel prognostic marker and potential therapeutic target for mCRC patients.

CD44: A New Prognostic Marker in Colorectal Cancer?

“…Furthermore, in our recent study, high CD44 expression was significantly associated with higher proliferative activity of CRC and poor prognosis. CD44 overexpression was also associated with clinically poor prognostic features: older age, inoperable disease, stage IV at diagnosis, mutated BRAF, and high-grade tumor [101,102]. Conversely, in a previous study, a statistically significant correlation was found between positive CD44 expression and left-sided tumors in an Egyptian population [103], which tend to be associated with a better prognosis than right-sided CRC localization [104,105].…”

Prediction of Response to Anti-Angiogenic Treatment for Advanced Colorectal Cancer Patients: From Biological Factors to Functional Imaging

“…Today, anti-angiogenic treatment represents a cornerstone of mCRC patient management in both the first-and second-line settings [3][4][5][6][7][8][9][10][11][12]. Unfortunately, the real OS gain from bevacizumab, aflibercept, and ramucirumab emerged from clinical trials and reallife data is about 1.4 to 1.6 months, which is quite marginal in the clinical history of a mCRC patient [3][4][5][6][7][8][9][10][11][12]16,17,[116][117][118][119]. The same concept applies even more to the role of regorafenib in further lines of treatment [20,120].…”

“…Around 20% of patients with CRC present with metastatic spread at diagnosis, and 30% among those with early stage disease will develop metastasis during their life [2][3][4]. Thanks to the development and introduction into clinical practice of new therapeutic strategies, in the last ten years the median overall survival (OS) of metastatic colorectal cancer (mCRC) patients has reached 35 months; however, OS at five years still does not exceed 20% [5,6]. Nowadays, the standard of care for mCRC treatment is represented by first-line fluoropyrimidine-based chemotherapy, either single agent or in combination with oxaliplatin or irinotecan (doublet or triplet regimen), plus biological agents targeting either vascular endothelial growth factor (VEGF, bevacizumab) or epidermal growth factor receptor (EGFR, panitumumab or cetuximab).…”

PRAME Promotes Cervical Cancer Proliferation and Migration via Wnt/β-Catenin Pathway Regulation

“…The amplification or overexpression of Cyclin D1 alters cell cycle progression and leads to tumorigenesis [ 37 ]. CD44 is involved in the process of heterogeneous adhesion of tumor cells and plays a role in promoting the invasion and metastasis of tumor cells [ 38 ]. Additionally, the intracellular domain of E-cadherin interacts with β-catenin, maintaining cell adhesion [ 39 ], and it was found that in PRAME-knockdown cells, E-cadherin expression was upregulated, and N-cadherin expression was downregulated; whereas in PRAME-overexpressed cells, E-cadherin expression was decreased, and N-cadherin expression was increased.…”