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Commentary |
From the Department of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
Recently, a variety of diseases have been explained by abnormality of signal transduction pathways, which must result in a revolution in not only pathology but biomedical sciences including development, stem cell science, and cancer. Some of these signaling pathways are Wnt, Hedgehog, and Notch pathways. These three have extended functions related to embryogenesis, maintenance of adult morphology, cancer, and degenerative disorders. Further, taking a cancer area for example, disrupted signaling of the pathways is not limited to a few specific types of cancer, but found in diverse origins of tumors. These suggest that these signaling pathways are pleiotropic in their activity.
In this issue of The American Journal of Pathology, Nakamura and colleagues1
present a comprehensive result of Wnt expression in orthopedic degenerative diseases such as rheumatoid arthritis (RA) and osteoarthritis (OA). In this commentary, the importance of Wnt signaling in cancer and stem cell science as well as its relevance to orthopedic disorders is examined. Interested readers are encouraged to visit the following Web pages on Wnt: http://www.stanford.edu/
rnusse/wntwindows.html and http://stke.sciencemag.org/.
Wnt Signaling and Its Roles in Cancer
Wnts are secreted glycoproteins that activate signal transduction pathways to control a wide variety of cellular processes such as determination of cell fate, proliferation, migration, and polarity. So far, at least three pathways have been identified in Wnt signaling: Wnt/ß-catenin (or canonical), Wnt/planar cell polarity, and Wnt/calcium pathways. However, the latter two are only incompletely understood and in this commentary Wnt/ß-catenin pathway is mainly discussed because it has been best investigated both in embryogenesis and cancer.
Wnt signaling research started from studies of abnormal morphology of wingless flies. Wnts are evolutionally well conserved and have been identified from hydra to humans. The human Wnt family constitutes 19 genes. Gene disruption analyses in mice demonstrated that each Wnt deficiency resulted in various kinds of different phenotypes, implying Wnt signaling is important also in organogenesis of mammals.
Wnt signaling is misregulated in diverse tumors.2 For instance, Wnts are overexpressed in non-small cell lung cancer, gastric cancer, head and neck squamous cell carcinoma, colorectal carcinoma, and ovarian carcinoma, but they are down-regulated in breast cancers. Secreted frizzled related proteins (sFRPs) are down-regulated in breast cancer but overexpressed in prostate cancer. Although detailed mechanisms are unknown of why they are overexpressed in one tumor and down-regulated in another, the pleiotropism of Wnt signaling is evident. Remembering Wnt signaling abnormality in so many kinds of cancer, we can easily adopt that "one of the most striking recent insights into the molecular basis of cancer has been the realization that key pathways controlling embryonic development are subverted in a wide range of tumors. Cancer can no longer be viewed purely in terms of a network of oncogenes and tumor suppressor genes."3
Stem Cells and Wnt Signaling: Control of Proliferation and Differentiation
We usually assume that cellular proliferation is antagonistic to cellular differentiation. This notion is largely appropriate because in embryogenesis undifferentiated cells proliferate to make tissues/organs while terminally differentiated cells do not grow any more. The notion may also agree with a common observation for cancer: poorly differentiated cancer cells proliferate more rapidly than well-differentiated ones. Wnt is thought to be involved in proliferation. Then, how does it contribute to differentiation?
Relations of cellular proliferation to differentiation are not straightforward. There is an interesting example in colon. Forced expression of a gene, Hath 1, associated with goblet cell differentiation can reduce the tumorigenicity of a colorectal cancer cell line.4 As pointed out by a recent review on Wnt signaling and tumor,2 this indicates the importance of down-regulation of genes associated with terminal differentiation. However, there is evidence against it. Thyroid transcription factor-1 (TTF-1) is a differentiation marker of type 2 pneumocyte because, as commonly observed, its protein expression is seen in almost all well-differentiated adenocarcinomas of the lung and only rarely in poorly differentiated ones. But unexpectedly the majority of small cell lung cancer, a highly malignant and rapidly proliferating tumor, also expresses TTF-1.5 Therefore, proliferation is certainly not just opposite to differentiation.
It has been recently revealed that Wnt signaling plays a pivotal role in proliferation of stem cells. Disruption of ß-catenin/TCF-4 activity in colorectal cancer cells induced a G1 arrest and blocked a program of proliferative compartment of colon crypts, and also it induced an intestinal differentiation program.6 The same research group further demonstrated that disruption of EphB/ephrin genes allocates cell populations within the intestinal epithelium and, in EphB/EphB3-null mice, the proliferative and differentiated populations intermingled.7 This indicates that ß-catenin and TCF couple proliferation and differentiation to the sorting of cell populations through the receptor system. Also in the hematopoietic system, Wnt signaling is very important for stem cell self-renewal.8 In most mouse hematopoietic stem cells, ß-catenin was activated and the hematopoietic stem cell population expanded in long-term cultures. Expression of Wnt signaling inhibitors such as axin led to inhibition of hematopoietic stem cell growth. These findings implicate that Wnt signaling works for hematopoietic stem cell homeostasis. Unexpectedly, however, inactivation of the ß-catenin gene in bone marrow progenitors does not impair their ability to self-renew and reconstitute all hematopoietic lineages (myeloid, erythroid, and lymphoid),9 implying Wnt signaling is dispensable.
Interactions of Hedgehog (hh), Notch, and Wnt pathways are a complex but interesting and emerging issue. So far we believed that mutations in cancer activate the hh and Wnt pathways and induce limitless cell proliferation.10 Indian hh, however, was reported recently to be an antagonist of Wnt signaling in colon,11 proposing a model where Ihh produced in terminally differentiated crypt-surface cells of colon regulates differentiation and inhibits Wnt signaling of the crypt-base cells, and Wnt produced in the crypt-base (ie, precursor) cells negatively regulates Ihh signaling. In colon carcinogenesis, APC mutations activate Wnt signaling and subsequently suppress Ihh signaling. Related to this, there is an interesting comparison between colon and sebaceous glands.3 In sebaceous glands, Ihh promotes differentiation by stimulating the proliferation of committed progenitors12 whereas, in colon, differentiation is promoted through an inhibition of proliferation. Relationships between differentiation and proliferation seem different in different tissues.
Bone Formation, Arthritis, and Wnt Signaling
As is well reviewed by Westendorf and colleagues,13 Wnt signaling promotes bone accrual. Also, disruption of Wnt signal-transducing proteins causes inherited disorders in humans: familial adenomatous polyposis (APC), familial exudative vitreoretinopathy with retinal angiogenesis (FZD4 and LRP5), tetra-amelia (Wnt3), osteoporosis pseudoglioma syndrome (LRP5), high bone mass disorders (LRP5).13 In the latter two diseases, LRP5 is differently mutated, which is a good example of genotype-phenotype relationships. Interested readers are encouraged to look at the above review and each original publication cited there. The review is particularly instructive because many unknown issues are explicitly stated as well as known ones.
Unfortunately, Wnt signaling is investigated only sparsely in orthopedic areas, including RA and OA although such arthritis is a leading cause of disability in elderly people. The first results on Wnt signaling in RA were reported, examining Wnt1, 5a, 10b, 13, frizzled (fz) 2, 5, and demonstrating higher mRNA expression of Wnt5a in RA than in OA.14 The result is not in concert with that of Nakamura and colleagues,1 which showed up-regulation of Wnt7b in RA synovium rather than Wnt5a. Also, another secreted factor in Wnt signaling, sFRP, was examined in RA and OA synovial cells. Among the five sFRP genes, sFRP1 and sFRP4 were expressed predominantly in fibroblast-like cell-rich populations whereas sFRP3 was expressed predominantly in macrophage-rich populations.15 The result suggests sFRP1, sFRP3, and sFRP4 play different roles in synovitis development.
Relationships between Wnt signaling and extracellular matrix proteins are interesting because fibroblast-like synovial cells of RA produce increased extracellular proteins. The role of Wnt1-like molecules was analyzed if the molecules regulated expressions of matrix proteins. The results indicated that the Wnt/ß-catenin pathway regulated fibronectin and metalloproteinase expression in RA fibroblast-like synoviocytes.16
Studies of CCN (connective tissue growth factor/cysteine-rich protein 61/nephroblastoma overexpressed) family members are another aspect of RA research. WISP3, a member of Wnt inducible signaling pathway proteins, has a microsatellite region in its coding region that is susceptible to mutation and results in protein truncation. There is an interesting report demonstrating that the WISP3gene expression was much higher in RA than OA with no increased protein expression and that mutations of the microsatellite were seen both in RA and OA.17 RA is characterized by synovial cell activation persisting even after anti-inflammatory therapy. From this viewpoint, the result was unpredictable.
Conclusion
Signal transduction studies are progressing rapidly in a wide variety of areas of biomedical research, although there are not many in the orthopedic fields. As pointed out from long ago, RA is similar to cancer because cells of both lesions proliferate autonomously and both cells are sensitive to cancer drugs such as methotrexate. Wnt signaling analysis may approach to underlying mechanisms of RA just like in cancer research. Results by Nakamura and colleagues1 will be a take-off point to much more comprehensive or in-depth studies. Also, it should be emphasized that signal transduction studies directly result in development of therapeutics.
Footnotes
Address reprint requests to Yuichi Ishikawa, Department of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550, Japan. E-mail: ishikawa{at}jfcr.or.jp
This commentary relates to Nakamura et al, Am J Pathol 2005, 167: 97–105, published in this issue.
Accepted for publication March 18, 2005.
References
This article has been cited by other articles:
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  A N A Milne, R Carvalho, M Jansen, E K Kranenbarg, C J H van de Velde, F M Morsink, A R Musler, M A J Weterman, and G J A Offerhaus Cyclin E low molecular weight isoforms occur commonly in early-onset gastric cancer and independently predict survival J. Clin. Pathol., March 1, 2008; 61(3): 311 - 316. [Abstract] [Full Text] [PDF]
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