Targeted Approaches to Inhibit Sialylation of Multiple Myeloma in the Bone Marrow Microenvironment

Abstract

Aberrant glycosylation modulates different aspects of tumor biology, and it has long been recognized as a hallmark of cancer. Among the different forms of glycosylation, sialylation, the addition of sialic acid to underlying oligosaccharides, is often dysregulated in cancer. Increased expression of sialylated glycans has been observed in many types of cancer, including multiple myeloma, and often correlates with aggressive metastatic behavior. Myeloma, a cancer of plasma cells, develops in the bone marrow, and colonizes multiple sites of the skeleton including the skull. In myeloma, the bone marrow represents an essential niche where the malignant cells are nurtured by the microenvironment and protected from chemotherapy. Here, we discuss the role of hypersialylation in the metastatic process focusing on multiple myeloma. In particular, we examine how increased sialylation modulates homing of malignant plasma cells into the bone marrow by regulating the activity of molecules important in bone marrow cellular trafficking including selectins and integrins. We also propose that inhibiting sialylation may represent a new therapeutic strategy to overcome bone marrow-mediated chemotherapy resistance and describe different targeted approaches to specifically deliver sialylation inhibitors to the bone marrow microenvironment.

Sialic acids in gynecological cancer development and progression: Impact on diagnosis and treatment

“…These findings are consistent with a growing body of literature demonstrate the hypersialylation and increased expression of sialylated antigens in prostate, breast, bladder, and testicular cancer and malignancies in the bone marrow 79‐86 . Generally, there were many similarities between gynecological cancers and other cancers, whereas the type of sialyltransferases that are overexpressed varied per cancer type.…”

“…These findings are consistent with a growing body of literature demonstrate the hypersialylation and increased expression of sialylated antigens in prostate, breast, bladder, and testicular cancer and malignancies in the bone marrow. 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 Generally, there were many similarities between gynecological cancers and other cancers, whereas the type of sialyltransferases that are overexpressed varied per cancer type. Using nanotechnology like surface‐enhanced Raman spectroscopy, sialic acid has been found in saliva, blood and cancer tissue of breast cancer patients, indicating its potential to be a highly sensitive and specific (noninvasive) biomarker for the screening of breast cancer in women.…”

ST8SIA1 inhibits the proliferation, migration and invasion of bladder cancer cells by blocking the JAK/STAT signaling pathway

“…that mediates important biological functions (10). It has been demonstrated that abnormal sialylation is closely associated with malignant brain tumors and multiple myeloma, and is usually accompanied by changes in the expression levels of sialyl transferases (STs) (11,12).…”

A Comprehensive Biological and Clinical Perspective Can Drive a Patient-Tailored Approach to Multiple Myeloma: Bridging the Gaps between the Plasma Cell and the Neoplastic Niche

“…erefore, interfering with sialylation may promote translational navigation of the milieu-drug resistance boundaries and define alternative combinatorial treatment strategies bringing sialylation inhibitors to the MM-stroma interface [30]. us, nanotechnologically engineered tools provided next-generation strategies for tailored anti-MM therapy by optimization of pharmacokinetics and pharmacodynamics profile of conventional chemotherapeutic agents [31].…”

“…Currently, delivery systems employing the sialylation inhibitor 3Fax-Neu5Ac encapsulation in combination with BMA are intensively investigated, in order to potentially block MM homing and enhance drug efficacy as well. In frame of this thinking, Natoni et al [30] have shown that BMSCs can nurse MM by shaping an immune-tolerogenic milieu and uncovered sialylation as an actionable mechanism to boost the immune response [30].…”