Prostate cancer in bone: Importance of context for inhibition of matrix metalloproteinases Page: 2 of 6
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Prostate cancer is the second most common cause of cancer death in American men.
Once metastasis has occurred, there is no curative treatment, and the search for effective
therapies for prostate cancer and, in particular, for metastasis to bone is hampered by a
lack of suitable animal models of the disease.
In this issue of the Journal, Nemeth et al. (1) address aspects of these two difficult issues.
They describe the use of the human fetal bone/severe combined immunodeficient (SCID)
mouse model to explore the role of matrix metalloproteinases (MMPs) in metastasis of
prostate cancer to bone and the ability of the broad-spectrum MMP inhibitor batimastat to
reduce bone disease.
Most research into human prostate cancer uses just three cell lines, PC3, DU-145, and
LnCaP. After subcutaneous inoculation into immunocompromised mice, these lines grow
as tumors but do not metastasize. Orthotopic inoculation can result in some limited
metastasis, but still there is the unresolved issue of human tumor tissue in a murine host.
The mouse prostate reconstitution model is a step forward, in that normal prostate
epithelial cells are transformed with myc and/or ras, mixed with normal mesenchymal
cells, and inoculated into the renal capsule of recipient mice (2). These mice develop
metastatic lesions in the lung, liver, mesentery, and bone. Elegant as the model is,
however, this is an artificial transformation. Like all other models where single or
multiple oncogenes are overexpressed, the events do not necessarily mimic the complex
processes leading to prostate or other cancers.
Cher and colleagues (3) used a different approach. SCID mice were implanted with
fragments of fetal human bone before the introduction of human prostate cancer cell lines
intravenously or directly into the human bone. Tumors developed in the human bone
cavity but not in the mouse skeleton. A similar system involving non-obese diabetic
(NOD)/SCID mice implanted with adult human bone fragments has also been described
recently (4). While these models can be used to explore prostate cancer growth potential
in bone, they are not useful for exploring the metastatic events that result in tumor cells
establishing in the bone environment. Tumor cells can colonize the human bone fragment
after either intravenous injection or direct injection into the bone fragment but not after
growth of a primary tumor. The models do, however, avoid the incompatibility issue of
human tumor cells in murine stromal tissue. A final point that distinguishes the few
existing prostate cancer models from the real disease is the fact that PC3 and DU-145
tumors are osteolytic, whereas those of LnCaP are both osteolytic and osteoblastic (3).
The metastases of human prostate cancer are predominantly osteoblastic or mixed blastic
and lytic.
Nemeth et al. (1) demonstrate that batimastat, a broadspectrum MMP inhibitor, can
prevent the loss of mineralized bone and can reduce the number of osteoclasts recruited
to the bone surface after injection of PC3 cells directly into the human bone marrow.
Batimastat treatment was accompanied by a reduction in the proportion of proliferating
PC3 cells but this was not obviously due to increased apoptosis or reduced angiogenesis.
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Bissell, Mina J.; Le Beyec, Johanne & Anderson, Robin L. Prostate cancer in bone: Importance of context for inhibition of matrix metalloproteinases, article, September 17, 2002; Berkeley, California. (https://digital.library.unt.edu/ark:/67531/metadc742303/m1/2/: accessed April 19, 2024), University of North Texas Libraries, UNT Digital Library, https://digital.library.unt.edu; crediting UNT Libraries Government Documents Department.