Mutational drivers of cancer cell migration and invasion

Abstract

Genomic instability and mutations underlie the hallmarks of cancer-genetic alterations determine cancer cell fate by affecting cell proliferation, apoptosis and immune response, and increasing data show that mutations are involved in metastasis, a crucial event in cancer progression and a life-threatening problem in cancer patients. Invasion is the first step in the metastatic cascade, when tumour cells acquire the ability to move, penetrate into the surrounding tissue and enter lymphatic and blood vessels in order to disseminate. A role for genetic alterations in invasion is not universally accepted, with sceptics arguing that cellular motility is related only to external factors such as hypoxia, chemoattractants and the rigidity of the extracellular matrix. However, increasing evidence shows that mutations might trigger and accelerate the migration and invasion of different types of cancer cells. In this review, we summarise data from published literature on the effect of chromosomal instability and genetic mutations on cancer cell migration and invasion.

Fig. 1. The model of cancer cell invasion.

Cancer invasion is the first step of the metastatic cascade. Tumour cells penetrate the basement membrane and invade the surrounding tissues using two modes of movement—individual and collective invasion. Invading tumour cells reach the blood vessel, enter the blood flow and disseminate, eventually giving rise to secondary tumours.

Fig. 2. Chromosomal instability and cancer invasion.

Chromosomal instability (CIN) is one of the cancer hallmarks and plays an important role in tumour cell migration and invasion. CIN can be represented by gain or loss of whole chromosomes (numerical CIN) and chromosomal rearrangements (structural CIN). Loss of heterozygosity (LOH) that can be attributed to numerical and structural CIN simultaneously, depending on the type of genomic changes resulting in the allele loss, affects the invasive potential of tumour cells. Polyploidy defined as the presence of additional sets of chromosomes drastically changes the genetic landscape of tumour cells, endowing them with high invasive potential. Polyploid giant cancer cells (PGCCs) are found in various cancers and show extreme tumorigenic, invasive and metastatic potential. Aneuploidy when chromosomes can be lost (monosomy) or gained (trisomy) can have different effects on tumour cell invasion: from attenuation of migratory behaviour to its enhancement. Different gene fusions arising from various chromosomal rearrangements affect tumour cell motility through diverse signalling pathways and mechanisms. Amplification defined as a copy number increase of a certain region of the genome leads to enhanced gene expression and, if a gene positively regulates cellular motility, it can accelerate cancer invasion.

Fig. 3. Gene alterations and cancer invasion.

Various gene mutations can affect tumour cell migration and invasion. Genes responsible for genome maintenance are frequently mutated in cancers; however, only a few of them can influence tumour cell motility, the main player here being TP53 and its diverse mutant forms. Alterations in genes that play a role in cell survival affect a variety of cellular processes and signalling pathways underlying cell migration. Mutations in genes encoding regulators of the actin cytoskeleton, adhesion, proteolysis and EMT directly influence the ability of tumour cells to migrate and invade.

Fig. 4. Intratumoural morphological heterogeneity of breast cancer as a model for studying the mechanisms of tumour cell invasion.

Intratumoural morphological heterogeneity of invasive carcinoma of no special type, the common histological type of breast cancer, is represented by various types of architectural arrangements of tumour cells that significantly differ in the transcriptomic profile, namely in the expression of genes involved in EMT and enrichment of cancer invasion signalling pathways. Tubular and alveolar structures are similar in epithelial and mesenchymal gene expression patterns. Solid structures demonstrate an increase in mesenchymal markers but retain epithelial features. Trabecular structures display a pronounced mesenchymal phenotype and a dramatic decrease in epithelial traits. Small groups of tumour cells and single tumour cells show a strong mesenchymal phenotype and the significant enrichment of cancer invasion signalling pathways. Torpedo-like structures have been recently identified to be associated with breast cancer metastasis through the activity of kinesin-14 (KIF14), mitochondria-eating protein (Mieap) and ezrin (EZR) that are known regulators of tumour cell motility and invasion. However, the EMT degree of torpedo-like structures remains to be elucidated. Based on these data, it can be hypothesised that tubular and alveolar structures are less invasive, whereas solid, trabecular and torpedo-like structures, as well as small groups of tumour cells and single tumour cells, are highly invasive. In addition, considering the architectural features, solid, trabecular and torpedo-like structures, as well as small groups of tumour cells, can be attributed to collective cancer cell invasion, whereas single tumour cells—to individual cancer cell invasion.