Lamins are multifunctional proteins that are often aberrantly expressed or localized in tumours. Here, we endeavour to assess their uses as cancer biomarkers: to diagnose tumours, analyse cancer characteristics and predict patient survival. It appears that the nature of lamin function in cancer is very complex. Lamin expression can be variable between and even within cancer subtypes, which limits their uses as diagnostic biomarkers. Expression of A-type lamins is a marker of differentiated tumour cells and has been shown to be a marker of good or poor patient survival depending on tumour subtype. Further research into the functions of lamins in cancer cells and the mechanisms that determine its patterns of expression may provide more potential uses of lamins as cancer biomarkers.

Lamins as multifunctional proteins

Study of the nuclear lamina is becoming increasingly popular, due to the discovery of the numerous and complex roles of lamins in normal and diseased cells. Mutations in LMNA, the gene encoding A-type lamins, lead to a wide range of degenerative diseases termed laminopathies [1]. Lamins are type V intermediate filament proteins that bind together to form a filamentous meshwork encompassing the nucleoplasmic side of the nuclear envelope. Three genes are known to encode lamin proteins in human somatic cells: A-type lamins (A, AΔ10 and C) are alternatively spliced products of LMNA [2,3], and B-type lamins are encoded by LMNB1 (lamin B1) [4] and LMNB2 (lamin B2) [5]. B-type lamins are essential for cell survival [6]. Lamins B1 and B2 are expressed in most cells, although lamin B2 is more ubiquitous than lamin B1 [7]. A-type lamins, however, are normally only expressed in differentiated cells [7].

Lamins play a role in a myriad of cell processes implicated in tumour progression, such as control of nuclear architecture, regulation of gene expression, apoptosis, senescence and chromatin organization and segregation [1]. Therefore the effects of alterations on lamin expression or localization in tumour cells are particularly complex.

Lamins as diagnostic biomarkers

Numerous studies have tried to elucidate the relationship between lamin expression and cancer subtype by investigating the changes in lamin expression in malignant cells and tissue sections. Expression levels of lamins are often but not always variable in tumours.

As B-type lamins are necessary for cell survival [6], at least one B-type lamin is always present in a malignant cell. Variable expression levels are present in some tumour subtypes: expression is usually found to be reduced [8,9], but increased lamin B1 expression has also been shown in prostate cancer and in HCC (hepatocellular carcinoma) [1012]. The presence of B-type lamins in most normal and tumour cells renders them poor diagnostic biomarkers for many cancer subtypes. However, lamin B1 has the potential to be used as a diagnostic biomarker to detect HCC from an early stage, as it is overexpressed in early and late stage HCC when compared with non-malignant controls (P<0.0001). Lamin B1 mRNA was present in plasma of HCC patients and was found to detect early stage HCCs with a sensitivity of 76% and a specificity of 82% [12].

As with B-type lamins, there is no simple overall pattern of A-type lamin expression in cancer and frequently no consistent patterns are observed between cancer subtypes. Many studies show lamin A/C to be down-regulated in tumour cells [8,9,13], but expression is also frequently positive or up-regulated [8,14,15]. Often expression levels can vary dramatically even within cancer subtypes; for example, in colorectal and BCCs (basal cell carcinomas), A-type lamin expression can be positive [13,14,16], reduced [9,13] or negative [9,13,16] in tumour tissue.

The presence of variable A-type lamin expression in most tumour subtypes suggests that, in most cases, A-type lamins may not be useful as diagnostic biomarkers. Nevertheless, cell-type-specific lamin A expression may be valuable as a diagnostic biomarker for detecting some cancers such as skin cancer. In non-cancerous skin, lamin A is not expressed in basal layers of the epidermis. However, in the apparently normal epidermis covering SCC (squamous cell carcinoma) and BCC, lamin A was found to be present in the basal layer [14].

Lamin A/C has been shown to aberrantly localize to the cytoplasm in some lung carcinomas, colon adenomas and adenocarcinomas, pancreatic and gastric cancers [8,9,16], whereas lamin B1 was localized to the cytoplasm in colon and lung cancers [9]. Lamin C was localized to the nucleolus in BCC and adrenal cortex carcinoma [13,14,17]. A number of studies have shown that lamins are present in the nucleoplasm in addition to the nuclear envelope in non-tumour cells [1820]. Therefore the detection of lamins in the cytoplasm is more likely to function as a diagnostic marker than the detection of lamin C in the nucleolus.

Lamins as markers of tumour characteristics

Proliferating epithelial cells contain low levels of A-type lamins [7] and overexpression of A-type lamin expression has been shown to inhibit cell proliferation [21]. However, data on the relationship between A-type lamins and proliferation in cancer cells are currently inconclusive. In BCC, highly proliferative cells were negative for expression of lamin A, whereas slow-growing tumours were negative for expression of lamin C [13]. Ki67 and lamin A/C expression were found to be mutually exclusive in approx. 80% of Hodgkin's disease cells [22]. However, co-expression of lamin A and Ki67 was found in 56% of proliferating SCC cells and in 62% of proliferating BCC tumour cells [14]. It appears that too little is known about the patterns of A-type lamin expression in proliferating tumour cells for it to be used as a marker for cell proliferation.

In non-cancerous tissue, A-type lamins are generally only expressed in differentiated cells [7,23] and lamin B1 has been shown to be reduced in some differentiated cells [7,24]. The link between B-type lamin expression and differentiation appears to vary with tumour subtype. B-type lamins were expressed in TGCTs (testicular germ cell tumours) regardless of the degree of differentiation [24], whereas well-differentiated SCCs showed reduced expression of lamins B1 and B2 compared with poorly differentiated tumours [25]. The presence of A-type lamins is often used to demarcate differentiated tumour cells. Down-regulation of A-type lamins in poorly differentiated tumours has been shown in many tumour subtypes such as SCC [25] and gastric carcinoma [26]. A study of TGCTs [24] showed that differentiated non-seminomas were positive for lamins A/C, only lamin C was expressed in EC (embryonal carcinoma), and poorly differentiated seminomas were negative for lamins A/C. It is understood that, in general, the poorer the differentiation of tumour cells, the worse the prognosis. More work needs to be carried out to assess the potential for expression of lamin A/C to act as a prognostic biomarker by using large patient cohorts to assess survival and the absolute degree of correlation of expression and differentiation status.

Lamins as prognostic biomarkers

Little is known about the link between lamin B expression in cancers and prognosis, although it has been shown in one study that an increase in lamin B in prostate cancer strongly correlates with the Gleason score (P=0.001), which is a predictor of prognosis [10].

Much more work has been carried out into the relationship between A-type lamins and cancer prognosis. Some studies point to a lack of lamin A/C expression as being a sign of poor prognosis. CpG island promoter hypermethylation, which silences LMNA and leads to loss of lamin A/C expression in nodal diffuse large B-cell lymphoma, has been correlated with a decrease in overall survival (P=0.0005) [27]. Moreover, a recent study has revealed that patients with gastric carcinoma cells containing down-regulated lamin A/C expression have poorer prognosis compared with those expressing lamin A/C (P=0.034) and that lamin A/C expression is an independent prognostic factor [26]. However, Willis et al. [16] unexpectedly discovered that patients with CRC (colorectal cancer) tumours expressing lamin A/C were almost twice as likely to die from the cancer compared with clinicopathologically identical patients with tumours showing negative expression of lamin A/C (P=0.005). A-type lamins are therefore potential biomarkers of poor prognosis in CRC.

It has been suggested that the poorer prognosis of CRC patients with lamin A expressing tumours may be linked to the discovery that lamin A is a marker of colonic stem cells [16] as cancer cells with characteristics of stem cells may be more aggressive [28]. The presence of CSCs (cancer stem cells) has been reported in several subtypes of cancer, such as breast [29], colon [28] and brain [30]. The CSC model describes a hierarchical system in which only a small population of cancer cells, namely the CSCs, are able to initiate and maintain tumour growth. This contrasts with the stochastic theory in which every cancer cell is capable of initiating a tumour [31]. CSCs maintain their aggressive properties as they are capable of self-renewal and differentiation [31].

However, lamin A may not be a universal marker of stem cells. In TGCTs, expression of lamin C but not lamin A indicates the presence of EC cells, the stem cells of non-seminomas. Determining the percentage of EC cells present in non-seminomas has been proposed as a potential prognostic marker for TGCTs [24].

These results demonstrate once more the complex role of lamins in cancer, and that the use of A-type lamins as prognostic biomarkers may depend greatly on the subtype of cancer involved.

A-type lamins and cell motility

A potential mechanism by which the expression of lamin A leads to poor prognosis of CRC patients has been elucidated. Willis et al. [16] found that expression of lamin A promotes increased cell motility. In wounding assays, wound closure was seven times faster in cells transfected with GFP (green fluorescent protein)–lamin A compared with control cells transfected with GFP alone. Lamin A was shown to control a pathway in which up-regulated expression of T plastin, an actin bundling protein, led to down-regulated expression of the cell adhesion molecule E-cadherin, resulting in increased cell motility [16]. Loss of E-cadherin and expression of plastins are often hallmarks of tumours, correlating with invasive and metastatic behaviour [32,33]. These results may reveal a function of lamin A as a regulator of a pathway involving actin dynamics, cell adhesion and cell motility.

It has been recently discovered that the cytoskeleton is connected to the nucleus through LINC (linker of nucleoskeleton and cytoskeleton) complexes, formed through binding of KASH (Klarsicht/ANC-1/Syne homology) domain proteins such as nesprins to SUN (Sad1 and UNC-84 homology) domain proteins [34]. The nucleoplasmic regions of human SUN domain proteins bind to A-type lamins [35,36] and nesprins have been shown to bind to actin microfilaments [37], plectin [38], emerin [39] and A-type lamins [39,40]. This provides a pathway by which signals can travel from the outside of the cell to the nucleus. Lamin A expression may therefore control the reorganization of the cytoskeleton through its association with LINC complexes, causing alterations in cell migration. The increase in cell motility may be a cause of the poorer prognosis of CRC patients with lamin A-positive tumours.

Once again, however, it appears that the link between A-type lamins and cell motility is not the same in all cell types. Green tea extract has been shown to induce up-regulation of lamin A/C expression in lung cancer A549 cells leading to a decrease in cell motility [41].

Conclusion

Cancer is a vastly complex and heterogeneous disease, and lamins exhibit a multitude of functions within a cell; therefore expression levels of lamins vary greatly depending on the subtype and characteristics of tumour cells.

Research into the use of lamins as cancer biomarkers is still at an early stage and none are yet being used clinically. A- and B-type lamins have limited use as diagnostic biomarkers in many cancers, due to their variable expression patterns between and within cancer subtypes and the presence of at least one B-type lamin in every tumour and normal cell. However, they can function as diagnostic biomarkers in some cancers: B-type lamins can detect early stage HCC [12], lamin A can detect the presence of skin cancer [14] and the mislocalization of lamins to the cytoplasm can be indicative of a number of different cancers [8,9,16].

Lamins have the potential to be used as prognostic biomarkers because the factors analysed in the present review, namely differentiation state, proliferative capacity and cell motility, can all be used to determine tumour aggressiveness [42]. In some cancers, A-type lamins appear to act as tumour suppressors. Many tumour subtypes and poorly differentiated cells exhibit down-regulation of lamin A/C expression [8,9,13,16,25,26] and loss of lamin A/C correlates with poor prognosis in large B-cell lymphoma and gastric cancer [26,27]. Conversely, in CRC, tumour cells expressing lamin A/C are indicative of poor prognosis and cells expressing lamin A are more motile and stem-cell-like [16].

It is well known that differentiated tumour cells express A-type lamins, but it is also interesting to note that the pattern of expression of A-type lamins has also been shown to define stem cells in TGCT (presence of lamin C) [24] and normal colon (presence of lamin A) [16]. It is thought that A-type lamins play a role in the control of stem cell self-renewal and differentiation. Progerin, a truncated form of lamin A, activates downstream effectors of the Notch signalling pathway in human mesenchymal stem cells [43] and mutated lamin A inhibits differentiation of muscle stem cells [44,45]. As stem-cell-like cancer cells are likely to be more aggressive, A-type lamin expression has the potential to be used as a marker of stem cells and hence as a prognostic biomarker in certain cancer subtypes. It would be of merit to further research patterns of lamin expression in CSCs to investigate if any trends can be identified.

Many of the studies discussed in the present review appear to give conflicting results. This can in some cases be explained by a lack of statistical significance caused by small sample sizes or methodological differences. However, an important conclusion is simply that the nature of the relationship between lamins and cancer is extremely complex. It is important to carry out more large-scale clinical studies to truly assess the potential of lamins as cancer biomarkers. Unravelling the complex nature of lamin function and the mechanisms that control its expression in cancer could have great benefits for the detection and analysis of tumours and the management of cancer patients.

Nuclear Envelope Disease and Chromatin Organization 2009: Independent Meeting held at College of St Hild and St Bede, University of Durham, Durham, U.K., 22–23 April 2009. Organized and Edited by Chris Hutchison (Durham, U.K.).

Abbreviations

     
  • BCC

    basal cell carcinoma

  •  
  • CRC

    colorectal cancer

  •  
  • CSC

    cancer stem cell

  •  
  • EC

    embryonal carcinoma

  •  
  • GFP

    green fluorescent protein

  •  
  • HCC

    hepatocellular carcinoma

  •  
  • LINC

    linker of nucleoskeleton and cytoskeleton

  •  
  • SCC

    squamous cell carcinoma

  •  
  • SUN

    Sad1 and UNC-84 homology

  •  
  • TGCT

    testicular germ cell tumour

Funding

This work was supported by a grant from the J.G.W. Patterson Foundation and funds from the James Cook University Hospital.

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