Abstract
Decades of research have disclosed a plethora of alterations in protein glycosylation that decisively impact in all stages of disease and ultimately contribute to more aggressive cell phenotypes. The biosynthesis of cancer-associated glycans and its reflection in the glycoproteome is driven by microenvironmental cues and these events act synergistically toward disease evolution. Such intricate crosstalk provides the molecular foundations for the activation of relevant oncogenic pathways and leads to functional alterations driving invasion and disease dissemination. However, it also provides an important source of relevant glyco(neo)epitopes holding tremendous potential for clinical intervention. Therefore, we highlight the transversal nature of glycans throughout the currently accepted cancer hallmarks, with emphasis on the crosstalk between glycans and the tumor microenvironment stromal components. Focus is also set on the pressing need to include glycans and glycoconjugates in comprehensive panomics models envisaging molecular-based precision medicine capable of improving patient care. We foresee that this may provide the necessary rationale for more comprehensive studies and molecular-based intervention.
Highlights
Genetic and epigenetic alterations are considered primary causes of cancer development, with downstream phenotypic changes at the protein level being amongst the driving forces of cancer progression and dissemination
Proliferative signaling is sustained by stromal cells that supply mitogenic factors, while glycosylation promotes growth factor receptor activation and positively regulates intracellular kinases pathways
Tumor cells evade growth suppression by abrogating the suppressive role of adhesion complexes with the extracellular matrix (ECM), mostly by the action of stromal-derived proteolytic enzymes
Summary
Genetic and epigenetic alterations are considered primary causes of cancer development, with downstream phenotypic changes at the protein level being amongst the driving forces of cancer progression and dissemination. While specific details on the biosynthesis and diversity of cancer-associated glycans may be found in recent reviews [7, 8], the following sections attempts to highlight the transversal nature of glycans, glycoproteins, and glycan-binding proteins throughout currently accepted cancer hallmarks, with emphasis on the crosstalk between glycans and the stromal components of the tumor microenvironment (Figure 2) These comprehend: (i) sustained proliferative signaling; (ii) resistance to cell death; (iii) deregulated cellular energetics; (iv) evasion of growth suppressors; (v) genome instability and mutations; (vi) replicative immortality; (vii) induction of angiogenesis; (viii) activation of invasion and metastasis; (ix) tumor-promoting inflammation; and (x) immune escape [13]. We foresee that this may provide the necessary rationale for more comprehensive studies and molecular-based intervention
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