The nuclear envelope environment and its cancer connections

Abstract

Because of the association between aberrant nuclear structure and tumour grade, nuclear morphology is an indispensible criterion in the current pathological assessment of cancer. Components of the nuclear envelope environment have central roles in many aspects of cell function that affect tumour development and progression. As the roles of the nuclear envelope components, including nuclear pore complexes and nuclear lamina, are being deciphered in molecular detail there are opportunities to harness this knowledge for cancer therapeutics and biomarker development. In this Review, we summarize the progress that has been made in our understanding of the nuclear envelope and the implications of changes in this environment for cancer biology.

Figure 1. Morphological changes at the nuclear envelope associated with cancer

Although tumours of different types show distinct morphological features, enlarged nuclei are characteristic of many cancer cells (compare the area indicated by square brackets in normal breast duct (part a) to invasive ductal carcinoma (part b)). At least in some cases, this increase in nuclear volume corresponds to aberrantly increased chromosome content with concomitant expansion of the nuclear periphery. Another hallmark of many cancer cells that is observed using haematoxylin and eosin staining is irregularity in nuclear contour, in the form of both indentations and protrusions. The invasive ductal breast carcinoma in part b shows an atypical invagination of the nucleus (indicated by an arrow). Changes in the appearance of chromatin, both at the nuclear periphery and in the nucleus interior — evident in part b — are also important criteria in diagnostic cytology. Nuclear grooves are characteristic of papillary thyroid cancer and their presence contributes to diagnosis (indicated by arrows in part c; this was imaged using a Papanicolaou stain of fine-needle aspirate). The enhancement of detection that is made possible with the use of immunofluorescence is illustrated in the comparison of haematoxylin and eosin staining (part d) versus immunofluorescence of lamin B (part e) in high-grade breast cancer. Changes to nuclear morphology indicate that cells may be neoplastic, but it is important to bear in mind that nuclear morphology is only one aspect of pathological assessment, which includes clinical context and often uses ancillary tests, such as immunohistochemistry, flow cytometry and molecular tests for the assessment of cellular aberrancies that are not detectable by light microscopy. Part d and part e are reproduced, with permission, from REF. © (2008) Romanian Academy Publishing House.

Figure 2. The nuclear envelope and factors that affect nuclear morphology

Two lipid bilayers surround the nucleus and are separated by a luminal domain that is contiguous with the endoplasmic reticulum (ER). The inner nuclear membrane (INM) and the outer nuclear membrane (ONM) are joined in a highly curved membrane domain at the site of nuclear pore complexes (NPCs) (BOX 2). The NPCs create selective channels that function together with soluble receptors to guide protein and RNA trafficking between the nucleus and cytoplasm. The nuclear lamina, a protein meshwork that is primarily comprised of lamin proteins (BOX 1), underlies the INM. This area is a hub for protein–protein interactions that link chromatin to the nuclear periphery, lamina to nuclear pores and residents of the INM to the peripheral environment of the nuclear interior^,. Just as important to nuclear structure and function is a series of interactions that create connectivity between the periphery of the nucleoplasm and the cytoskeleton. Specifically, the luminal domain of SUN domain-containing protein (SUN) family members residing in the INM interact with luminal domains of Klarsicht, ANC1, Syne homology (KASH) family members that are resident in the ONM. In turn, the cytoplasmic domains of KASH proteins contain specific sites of contact for actin, microtubules and intermediate filaments. This network of interactions has been termed the linker of nucleoskeleton and cytoskeleton (LINC) complex. LINC complex proteins also have a role in tethering centrosomes to the near vicinity of the ONM. Invaginations of the nuclear membrane, which are often observed in tumour cells, have been characterized more broadly and are referred to as the nucleoplasmic reticulum. More recently, these were further classified into type I invaginations, which affect the INM only, and type II invaginations, which involve the INM and the ONM together. Many processes and factors influence nuclear morphology (referred to in the box). BAF, barrier to autointegration factor; LAP2, lamina-associated polypeptide 2; LBR, lamin B receptor; NE, nuclear envelope.

Figure 3. Roles of the nuclear envelope subject to deregulation concomitant with changes in nuclear morphology

Myriad cellular activities are coordinated by a range of factors that are integral to or that are associated with the nuclear envelope. The permeability barrier and the scaffolding platform established by the nuclear envelope locally concentrate factors, permit regulated sequestration of their activity and allow spatially restricted post-translational modification. These events at the nuclear periphery control the activity, as well as the stability and the proper cellular localization of, components that are key to signalling, transcription, DNA repair, cell division, and cell shape and migration. Proteins of the nuclear periphery, such as nucleoporins (NUPs) and lamins, can also take on roles within the nucleoplasm and during mitosis. As a physical anchoring point for centrosomes and the cytoskeleton, proper function of the nuclear envelope is also crucial for various mechanical events, including those of cell division and cell migration. BAF, barrier to autointegration factor; cAMP, cyclic AMP; CBP, CREB-binding protein; CTCF, CCCTC-binding factor; EGF, epidermal growth factor; EPAC1, exchange protein directly activated by cAMP 1; GCL, germ cell-less; HDAC, histone deacetylase; HP1, heterochromatin protein 1; IGF, insulin-like growth factor; LAP2β, lamin-associated polypeptide 2β; LINC, linker of nucleoskeleton and cytoskeleton; NPC, nuclear pore complex; P, phosphorylation; SENP, sentrin-specific protease; SREBP1, sterol regulatory element-binding protein 1; TGFβ, transforming growth factor-β; UBC9, ubiquitin-conjugating enzyme 9.