Cell polarity signaling in the plasticity of cancer cell invasiveness

Abstract

Apico-basal polarity is typical of cells present in differentiated epithelium while front-rear polarity develops in motile cells. In cancer development, the transition from epithelial to migratory polarity may be seen as the hallmark of cancer progression to an invasive and metastatic disease. Despite the morphological and functional dissimilarity, both epithelial and migratory polarity are controlled by a common set of polarity complexes Par, Scribble and Crumbs, phosphoinositides, and small Rho GTPases Rac, Rho and Cdc42. In epithelial tissues, their mutual interplay ensures apico-basal and planar cell polarity. Accordingly, altered functions of these polarity determinants lead to disrupted cell-cell adhesions, cytoskeleton rearrangements and overall loss of epithelial homeostasis. Polarity proteins are further engaged in diverse interactions that promote the establishment of front-rear polarity, and they help cancer cells to adopt different invasion modes. Invading cancer cells can employ either the collective, mesenchymal or amoeboid invasion modes or actively switch between them and gain intermediate phenotypes. Elucidation of the role of polarity proteins during these invasion modes and the associated transitions is a necessary step towards understanding the complex problem of metastasis. In this review we summarize the current knowledge of the role of cell polarity signaling in the plasticity of cancer cell invasiveness.

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

“…The early stages of the invasion process, namely the crossing of the basement membrane and the gradual detachment from the primary tumor mass, are typically carried on by large and cohesive cohorts of tumor cells, in the form of clusters, strands, sheets or cords (collective migration). Although most of the cells within the invading cohort display an overt epithelial phenotype (including the maintenance of cell-cell adhesion), cells located at the leading front release matrix proteases and possess strong migratory abilities 11–13 . As cancer invasion proceeds, the migrating cell cohorts undergo a further dedifferentiation process, likely triggered by signals derived from the multiple mesenchymal and inflammatory cells populating the tumor stroma.…”

“…Ultimately, this process results in a gradual loss of epithelial features, and a concurrent acquisition of some mesenchymal traits. At this stage, a switch from collective to single-cell migration takes place, strikingly enhancing the efficiency of the invasion proces 12,13 . In other words, invasive cancer cells partly recapitulate an embryonic program known as epithelial-to-mesenchymal transition (EMT), through which epithelial cells dismantle cell-cell junctions, lose planar and apical-basal polarity, and eventually establish a front-rear axis, thus adopting an elongated, spindle-shaped morphology.…”

“…These interactions occur at the level of large, multi-protein adhesive structures known as focal adhesions, which are based on transmembrane integrins, and mechanically connect the ECM to the actin cytoskeleton. The formation of cell protrusions, and the continuous turnover of cell-matrix contacts generate strong traction forces that ultimately support cell movement 13,18,19 . In this context, it is worth mentioning that small GTPases belonging to the Rho family play a prominent role in orchestrating cell motility.…”

“…With regard to mesenchymal migration, Cdc42 is essential for establishing a front-rear polarity in the direction of movement and inducing filopodia extension, Rac1 promotes lamellipodia formation, and RhoA mediates the maturation of focal adhesions and drives the retraction of the cell rear 18,19 . In addition to lamellipodia and filopodia, the cell front is also equipped with other actin-rich extensions named invadopodia, wherein matrix proteases tend to cluster and exert their proteolytic activity 13 . Of note, both Cdc42 and RhoA are markedly involved in invadopodia assembly as well 20 .…”

MARK2 inhibits the growth of HeLa cells through AMPK and reverses epithelial-mesenchymal transition

“…Further investigations may elucidate these issues more clearly. Loss of cell polarity, along with the acquisition of motility and invasiveness, are regarded as typical phenomena during the epithelial-mesenchymal transition (EMT) process (41,42). Enforced expression of MARK2 inhibited the mesenchymal and stimulated an epithelial-like morphology with concomitant alterations in EMT markers expression, and reduced migration and invasion, thus causing the shift of the EMT balance in favor of an epithelial state.…”