Nuclear Matrix Proteins and Cancer
July 1, 1999 6 minutes read
Nuclear Matrix Proteins and Cancer
By Badrinath R. Konety, MD, and Robert H. Getzenberg, PhD
Cellular hallmarks of the transformed phenotype include abnormal nuclear shape, altered patterns of chromatic condensation, and the presence of abnormal nucleoli. Nuclear structural alterations are so prevalent in cancer cells that they are commonly used as a pathological marker of transformation for many types of cancer. Nuclear shape is thought to reflect the internal nuclear structure and processes and is determined, at least in part, by the nuclear matrix.1 The nuclear matrix has been demonstrated to play a central role in the regulation of important cellular processes such as DNA replication and transcription.2 The nuclear matrix is the framework or scaffolding of the nucleus and consists of the peripheral lamins and pore complexes, an internal ribonucleic protein network, and residual nucleoli.3 The nuclear matrix consists of approximately 10% of the nuclear proteins and is virtually devoid of lipids, DNA, and histones.4
The structural components of the nucleus are known to have a central role in the specific topological organization of DNA. DNA in the nucleus is not randomly organized, and although only approximately 10% of the DNA actually encodes proteins, only specific genes are positioned in a manner that permits the expression of both housekeeping and cell type specific genes. Nuclear structure is, therefore, involved in both this topological organization of DNA and the functional aspects that coincide with this organization.
The majority of known nuclear matrix proteins (NMPs) are common to all cell types and physiologic states. In addition, some NMPs appear to be unique to certain cell types or states, and NMPs have been shown to serve as a "fingerprint" of cell or tissue types. Mitogenic stimulation and the induction of differentiation have been demonstrated to alter the composition of nuclear matrix proteins and structure.5,6 Differences in NMP composition have been found in a number of human tumors, including prostate,7,8 kidney,9 breast,10 colon,11 head and neck,12 and bladder.13
Identification of Prostate Specific NMPs
Previously, we investigated the nuclear matrix protein composition in a rat model of prostate cancer. We initially examined the NMPs of the normal rat prostate in comparison with rat prostate adenocarcinoma lines from the Dunning R3327 rat model of prostate cancer. We demonstrated that the NMP composition of transformed cell lines differed significantly from their tissue of origin, and while these transformed prostate cell lines were almost entirely composed of a common set of NMPs, there were differences that would distinguish cell lines of different degrees of the transformed phenotype from one another.7 We have been successful at sequencing as well as raising antibodies against several of the prostate cancer specific NMPs and those that were able to differentiate metastatic and non-metastatic tumors. These prostate cancer specific NMPs are being developed as potential diagnostic/prognostic markers for prostate cancer.
In a similar fashion, we have also analyzed the NMP composition of human prostate tumor and normal human prostate tissue.8 We compared the NMP patterns for fresh prostate, benign prostatic hyperplasia (BPH), and prostate cancer from 21 men undergoing surgery for clinically localized prostate cancer or BPH. We identified, by molecular weight and isoelectric point, 14 different proteins that were consistently present or absent among the various tissues. One protein (PC-1), a Mr 56,000 protein with an isoelectric point of 6.58, appeared in all of 14 nuclear matrix preparations from different prostate cancer patient specimens and was not detected in normal prostate (0 of 13) or BPH (0 of 14).
Identification of Bladder Cancer Specific NMPs
The NMP composition of normal and tumor (transitional cell carcinoma) bladder tissue has also been analyzed.13 In the initial study, tumors of various grades and stages were used. Only tumor samples that could be clearly identified by the pathologist as containing approximately pure populations of the stated tumor grade were utilized. Normal bladder tissue samples that were obtained from organ donors were also analyzed. The NMPs were extracted and separated by high resolution two-dimensional gel electrophoresis. All tumors were found to express differences in their nuclear matrix composition when compared with the nuclear matrix composition of the matched normal tissue from the same bladder. There are several notable differences in nuclear matrix composition of the bladder tumor when compared to the normal tissue. We have identified six proteins (BLCA-1 to BLCA-6) that are present in all of the tumors and are absent in the adjacent normal tissue and three proteins (BLNL-1 to BLNL-3) that are found in all of the normal bladder tissue samples and are missing in the tumor samples. These differences appear to be unique to bladder cancer in that the molecular weights and isoelectric points of the proteins do not appear to correspond to those proteins previously reported to be different in prostate and breast cancers.13 We have also developed an immunoassay which can be used to detect the presence of one of the bladder-specific NMPs, BLCA-4, in the urine of patients with bladder cancer. This NMP is absent from the urine of normal individuals. We are in the process of developing an NMP-based diagnostic test for bladder cancer.
A diagnostic test for bladder cancer based on the detection of NMPs in the urine is currently available. The NMP22 test (Matritech Inc., Newton, MA) detects the presence of nuclear mitotic apparatus protein (NUMA), which is present in most dividing cells during mitosis. This protein however, is not specific for bladder cancer. The test has been used to detect bladder cancer in patients being monitored for recurrent disease after therapy for bladder cancer.14 While the test is more sensitive than urine cytology (the routine diagnostic test used to detect bladder cancer), it does not appear to have consistent specificity.
Identification of Renal Cancer Specific NMPs
Using a strategy similar to that employed in prostate and bladder cancer, NMPs unique to renal cell carcinoma have also been identified.9 Using matched normal and tumor kidney tissue obtained from 17 patients undergoing radical nephrectomy, five NMPs exclusive to renal cancer were identified. One NMP was found only in all the normal kidney samples examined. All of these NMPs were found to be different from those detected in other tumors. Further studies are necessary to determine if any of these NMPs can be used as diagnostic or prognostic markers for renal cell carcinoma.
The relative success of the NMP22 test suggests that nuclear matrix proteins can be used for the diagnosis of tumors by identifying the proteins in body fluids such as urine and serum. Similar but more sensitive and specific diagnostic tests are under development for cancers of the prostate, bladder, and kidney and are expected to become available in the near future. (Dr. Getzenberg is Director of Research, Prostate and Urologic Cancer Center, University of Pittsburgh Cancer Institute.)
References
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5. Dworetzky SI, Fey EG, Penman S, et al. Progressive changes in the protein composition of the nuclear matrix during rat osteoblast differentiation. Proc Natl Acad Sci U S A 1990;87:4605-4609.
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Nuclear matrix proteins:
a. are uniformly expressed in all cell types and tissues.
b. provide a scaffolding for specific topological organization of nuclear DNA.
c. differ in composition in various human tumors.
d. Answers b and c
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