Breaking the scale: how disrupting the karyoplasmic ratio gives cancer cells an advantage for metastatic invasion

Abstract

Nuclear size normally scales with the size of the cell, but in cancer this 'karyoplasmic ratio' is disrupted. This is particularly so in more metastatic tumors where changes in the karyoplasmic ratio are used in both diagnosis and prognosis for several tumor types. However, the direction of nuclear size changes differs for particular tumor types: for example in breast cancer, larger nuclear size correlates with increased metastasis, while for lung cancer smaller nuclear size correlates with increased metastasis. Thus, there must be tissue-specific drivers of the nuclear size changes, but proteins thus far linked to nuclear size regulation are widely expressed. Notably, for these tumor types, ploidy changes have been excluded as the basis for nuclear size changes, and so, the increased metastasis is more likely to have a basis in the nuclear morphology change itself. We review what is known about nuclear size regulation and postulate how such nuclear size changes can increase metastasis and why the directionality can differ for particular tumor types.

Cell size scaling laws: a unified theory

“…Our investigations thus link two seemingly distinct hallmark of cancers : the disruption of the cell size scaling laws such as the abnormal karyoplasmic ratio, historically used to diagnose cancer, and metabolic reprogramming, some cancer cells showing an increased consumption of their pool of glutamate and glutamine to fuel the TCA cycle and enhance their proliferation and invasiveness [50]. This may thus represent possible avenues for future research related to the variability of nucleus size in cancer cells [52]. Moreover, the large pool of metabolites is a robust feature throughout biology [28], making it one of the main causes of the universality of the cell size scaling laws observed in yeasts, bacteria and mammalian cells.…”

Nuclear Dynamics and Chromatin Structure: Implications for Pancreatic Cancer

“…A striking cytological feature of cancer cells is the frequently observed change in the karyoplasmic ratio (nuclear:cytoplasmic ratio). The karyoplasmic ratio is one of the prominent features used by histopathologists for cancer diagnosis and prognosis [290]. In cancers, the nuclear:cytoplasmic ratio typically increases; however, the functional aspect of this feature is not well-understood.…”

Lamin A and the LINC complex act as potential tumor suppressors in Ewing Sarcoma

“…Aside from molecular alterations, nuclear shape and size and chromatin conformation can provide parameters for cancer diagnostics, but the functional significance of these alterations in the context of EWS disease progression and metastatic processes is not yet fully clarified [ 3 , 4 ].…”

“…These observations support the concept that shape instability of the nuclear envelope is functionally relevant in aggressive malignancies, and has potential consequences for genome instability, tumor progression, and metastatization [ 5 – 8 ]. Nuclear envelope proteins play a key role in a variety of cellular pathways implicated in tumorigenesis and their altered expression has been detected in human cancers, often associated to an aggressive phenotype [ 4 , 9 , 10 ]. The nuclear envelope is formed by the nuclear membrane and the nuclear lamina, the latter being located beneath the inner nuclear membrane.…”