Maspin as a Prognostic Marker for Early Stage Colorectal Cancer With Microsatellite Instability

Abstract

Colorectal cancers are among the most common cancers and a leading cause of cancer death. In our pursuit to discover molecular markers for better characterization and precision theranostics of these cancers, we first conducted global deep proteome analyses and identified maspin (serpin B5, peptidase inhibitor 5) as an upregulated protein in tumor tissue. We then validated its expression in a large cohort of 743 patients with colorectal cancers of all stages and found that both cytoplasmic and nuclear expression varied widely between different patients. Comparison with clinicopathological features revealed that maspin expression levels correlate significantly only with mismatch repair (MMR) status but not with other features. To elucidate the prognostic significance of maspin, we analyzed two outcome-annotated cohorts, one of 572 early stage cancer patients and another of 93 late stage cancer patients. Kaplan-Meier survival, univariate, and multivariate analyses revealed that maspin overexpression predicts longer overall and disease-free survival for early stage microsatellite instability (MSI) subtype colorectal cancer, but there is no correlation with survival for patients with early stage cancer of the microsatellite stability (MSS) subtype or late stage cancer. Our study identifies maspin expression as an independent prognostic marker for risk stratification of early stage MSI subtype colorectal cancer and may provide guidance for improved therapeutic management.

Subcellular Expression of Maspin in Colorectal Cancer: Friend or Foe

“…Because the immune escape mechanisms of tumor buds are different in MSI cases [1], the budding degree is not as helpful in these carcinomas as it is for MSS carcinomas. Maspin upregulation in the tumor core of early stage MSI-H carcinomas seems to be rather an indicator for a longer overall and disease-free survival [4]. Some authors admit a nuclear overexpression [35] while others showed no significant association of subcellular expression with evolution or prognosis of MSI-H cases [4].…”

“…Being also known as the serpin B5 or peptidase inhibitor 5, maspin is an unsusual non-inhibitory member of the the serine protease inhibitor (serpin) superfamily [4,5]. Maspin gene is located to chromosome 18q21.3 of exon 2 and was firstly described by Zou et al in 1994 [5-7].…”

“…A review published in 2019 by Banias et al showed that, in normal organs and tissues, maspin can be present in epithelial and non-epithelial structures [6]. It can mark urothelium, squamous epithelium, basal cells of the prostate and bronchial epithelium, placental cyto-and syncytio-trophoblasts, fibroblasts, myoepithelial cells of the mammary gland, endometrium, mucosa of the gastrointestinal tract (esophagus, stomach, small intestine, colon and rectum), testis, thymus, as well as corneal keratocytes, epithelial and endothelial cells [4,5,7,[9][10][11][12]. Any human tissue might express maspin, mainly in the cytoplasm, secretory vesicles and cell membrane but the expression level is not similar [4,9].…”

“…Maspin can be down-or upregulated in tumors but the significance of these changes, correlated with maspin subcellular localization, compared with parental tissues, is far to be understood. Most of the published papers refers to maspin expression in carcinomas [4,6,16,17]. In the previously published reports, maspin was examined in particular in breast carcinomas and CRCs, but it was reported to also mark carcinomas of the oral cavity, esophagus, stomach, larynx, lung, pancreas, thyroid, prostate, ovary and urinary bladder [5,6,[17][18][19].…”

“…Decreased maspin increases the risk of tumor progression and occurrence of distant metastases [11,12,16,24,25]. In CRC maspin is even described as an immunogen or "autoantibody-inducing autoantigen" with immunomodulatory role [4,28,29]. The independent prognostic role of maspin is, however, not accepted by all of the authors [1,26].…”