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This Month in AJP |
Circulating Tumor Cells: Are They Capable of Metastasizing?
It is generally assumed that the detection of tumor cells in the blood of patients with non-hematological malignancies signifies a high probability of metastasis and unfavorable prognosis. Yet little information is available on the functional capabilities of circulating cells released from solid organ malignancies. Méhes et al (Am J Pathol 2001, 159:17–20) analyzed circulating breast cancer cells to determine whether those cells might be apoptotic. The cells were identified by automated fluorescence image analysis using cytokeratin (CK) and epithelial-type mucin (MUC1) as markers. These cells were detectable in 42% of blood samples from breast cancer patients but not in 25 patients who served as a control group. Apoptosis was assessed by changes in staining patterns of the CK marker, chromatin fragmentation and TUNEL positivity. With the exception of samples from one patient, the majority of circulating cells from breast cancer patients had an apoptotic phenotype. In 37.5% of peripheral blood samples in which circulating tumor cells were detectable, no intact cells were found. This work raises the possibility that a large proportion of circulating tumor cells released from non-hematological malignancies may not be viable and capable of establishing metastatic growth.
Down-Regulation of the Expression of Estrogen Receptor ß during Prostatic Carcinogenesis but not in Metastatic Sites
Most prostate cancers are initially responsive to
anti-androgens but often become refractory to this type of therapy.
Estrogens act on target tissues by binding to two types of receptors,
ER
and ERß, which appear to mediate different downstream
activities in prostate tissues. There are also indications that ERß
is the predominant receptor in the prostate and that anti-estrogens may
inhibit prostatic cell proliferation by interfering with ERß
signaling. Leav et al (Am J Pathol 2001, 159:79–92)
developed specific antibodies to ERß and compared the expression of
this receptor to that of ER as well as the androgen receptor in
normal dysplastic lesions and carcinomas in the human prostate. They
also measured receptor transcripts by reverse transcriptase-polymerase
chain reaction using tissue samples obtained by laser capture
microdissection. ERß was found to be predominantly localized in basal
cells while ER was mostly localized in stromal cells. ER-ß
expression was down-regulated during prostatic carcinogenesis in
high-grade dysplastic lesions and high-grade neoplasias. Surprisingly,
ERß was expressed in the great majority of prostate cancer metastases
in bone and lymph nodes. The new knowledge gained by studies on ERß
will help improve the treatment of prostate cancer with agents that act
on specific estrogen receptors.
Loss of 10q and PTEN in Anaplastic Oligodendrogliomas: Poor Prognosis Even with Response to Chemotherapy
Allelic loss of chromosome 10q is one of the most frequent alterations in gliomas. It has been detected in approximately 80% of glioblastomas, 37 to 75% of anaplastic astrocytomas, and 13 to 31% of anaplastic oligodendrogliomas. The 10q loss in malignant gliomas may involve three potential tumor suppressor genes: PTEN, DMBT1, and ERCC6. Sasaki et al (Am J Pathol 2001, 159:359–367) analyzed these three genes in a large number of patients with anaplastic oligodendrogliomas. Deletion mapping demonstrated 10q loss in 14 of 67 cases with the PTEN and DMBT1 region involved in all deletions. PTEN gene alterations were not associated with a poor response to chemotherapy, but were independent predictors of poor prognosis even in tumors that responded to chemotherapy.
Epidermal Hypertrophy, Hyperplasia, and Dermal Fibrosis Caused by Increased Expression of Cyclin-Dependent Kinase 4 (CDK4)
Progression through the G1 phase of cell cycle is regulated by cyclins and their associated kinases (CDKs). Members of the cyclin D family (D1, D2 and D3) can form complexes with CDK4 which is partially responsible for the phosphorylation of the retinoblastoma gene (Rb) and its subsequent inactivation. Rb phosphorylation releases the inhibition of transcription factors and other genes involved in the G1-S cell cycle transition. It is known that cyclins D1 and D2 have profound effects on cell proliferation and tumor development in various tissues. However, much less is known about the role that CDK4 by itself might have on cell cycle regulation. To study this problem, Miliani de Marval et al (Am J Pathol 2001, 159:369–379) developed transgenic mice that overexpressed CDK4 in the epidermis under the control of a keratin 5 promoter. These mice had increased epidermal proliferation with basal cell hypertrophy and hyperplasia. Overall, these abnormalities were much more extensive than those observed in transgenic mice that overexpress D-type cyclins. In addition, the CDK4 transgenics had severe dermal fibrosis and atrophy of subcutaneous adipose tissue. Increased expression of CDK4 did not alter the level of expression of D-type cyclins but most likely stimulated epidermal proliferation by binding and sequestering the cell cycle inhibitor p27. The results demonstrate that CDK4 can act independently from cyclins to stimulate cell proliferation by binding cell cycle inhibitors. Moreover, hyperproliferative epidermis may release growth factors that act to promote dermal fibrogenesis.
Alterations in TGF-ß1 Signaling in Myofibroblasts from Fibrotic Skin: Impairment of Smad3 Signaling
TGF-ß1 is a multifunctional cytokine that can inhibit cell
growth, stimulate the deposition of collagen and extracellular matrix
components, and act as an immune suppressor. The mechanisms that
determine TGF-ß1 effects on cell proliferation and fibrogenesis are
not completely understood. Reisdorf et al (Am J Pathol 2001,
159:263–272) studied TGF-ß1 response in myofibroblasts obtained
from fibrotic skin from pigs treated with 
radiation. Myofibroblasts
from these tumors showed a dissociation between the proliferative and
fibrogenic effects of TGF-ß1. In contrast to its effect on normal
skin fibroblasts, TGF-ß1 did not inhibit proliferation of
myofibroblasts. In addition, translocation of Smad3, one of the TGF-ß
receptor-activated proteins, was greatly impaired in myofibroblasts.
The results suggest that signaling through Smad3 is required for
TGF-ß1 effects on cell proliferation but not for its fibrogenic
activity.
Circulating Endostatin Released from the Liver Can Block Ocular Neovascularization
Neovascularization involves an imbalance between stimulators and inhibitors of endothelial cell growth. It is now recognized that endothelial cells in various tissues may differ in their phenotypic characteristics and may react differently to stimulators and inhibitors. Neovascularization plays an important role in diabetic retinopathy. Furthermore, choroidal neovascularization is responsible for severe visual loss in patients with age-related macular degeneration, a very common cause of visual impairment in patients over 60 years of age. The retina and choroid are highly specialized tissues with unique vasculatures that make it difficult to predict their response to inhibitors of neovascularization. Mori et al (Am J Pathol 2001, 159:313–320) demonstrate that circulating endostatin can nearly completely prevent choroid neovascularization in mice. In these experiments, mice were injected intravenously with adenovirus vectors containing a sequence coding for murine endostatin. These vectors localized primarily in the liver which became the source of circulating endostatin reaching levels which were approximately 10 times higher than normal. In these animals, circulating endostatin prevented choroidal neovascularization caused by laser photocoagulation and rupture of Bruch membrane. The work demonstrates that it is possible to inhibit ocular neovascularization by systemic administration of protein inhibitors contained in vectors that lodge in the liver.
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