Nonrandom involvement of chromosome 4 in the progression of rat prostatic cancer

Abstract

Owing to progression of the original spontaneous Dunning R-3327 rat prostatic cancer, a large series of transplantable prostatic tumors have been isolated that differ widely in their histological degree of differentiation, growth rate, androgen sensitivity, and metastatic ability. Using these parameters as criteria, the full spectrum of disease progression is represented within this Dunning system of rat prostatic cancers, ranging from slow-growing, well-differentiated, androgen-sensitive, nonmetastatic forms to fast-growing, anaplastic, androgen-independent, highly metastatic forms. Cytogenetic analysis of the two least progressionally advanced Dunning cancers (i.e., histologically well-differentiated, slow-growing, nonmetastatic variants) demonstrated no structural or numerical chromosomal aberration, suggesting that the initial development of prostatic cancer may not require detectable cytogenetic changes. In contrast, all 16 of the progressionally more advanced Dunning variants analyzed had a series of characteristic structural and/or numerical chromosomal aberrations that minimally involved chromosome 4. This nonrandom involvement of chromosome 4 was consistently observed regardless of whether the karyotype of the cancer was near-diploid or hyperaneuploid, suggesting that chromosome 4 aberrations are specifically involved in the progression of rat prostatic cancer. In addition, all four variants that were highly metastatic had, besides aberration of chromosome 4, structural aberrations involving chromosomes 1, 2, and 11. Of the 14 variants that did not have a high metastatic ability, only two had a similar aberrations involving chromosomes 1, 2, 4, and 11, suggesting that these specific chromosomal aberrations may be necessary, albeit not sufficient, for a high metastatic ability of rat prostatic cancers.

Suppression of invasive ability of highly metastatic rat prostate cancer by introduction of human chromosome 8

“…The AT6.2 cells were a highly metastatic, androgen-independent anaplastic subline from Dunning R-3327 rat prostate adenocarcinoma [10]. Six AT6.2-8 clones (i.e., AT6.2-8-1, -2, -3, -4, -5, and -6) were AT6.2 microcell hybrids containing human chromosome 8.…”

“…Tumor doubling time was used as the index of tumor growth rate and determined as previously described [10]. Five weeks after injection, mice were sacrificed and scored for lung metastases.…”

“…Several studies showed the relationship between rate of loss of heterozygosity (LOH) on chromosome 8p and tumor progression, and suggested that LOH on 8p was relatively late event in prostate cancer [3,4,8,9]. In our previous study, introduction of human chromosome 8 to a highly metastatic androgen-independent subline (AT6.2) from the Dunning R-3327 rat prostate cancer using microcell-mediated chromosome transfer resulted in sup-pression of metastasis without suppression of tumor growth rate or tumorigenicity after subcutaneous transplantation [10]. This suggests the presence of a metastasis-suppressor gene(s) for rat prostate cancer located on human chromosome 8, but the mechanism by which metastasis was inhibited in AT6.2-8 clones is unclear.…”

Identification of the rat homologue ofKAI1 and its expression in dunning rat prostate cancers

“…All of these sublines were derived from the slow-growing, nonmetastatic, androgen-responsive, well-differentiated H parental prostate cancer. The developmental history and characteristics of each of these sublines have been described previously [11,13,14]. All of these sublines, except for H, were grown in standard RPMI-1640 (M.A.…”

“…The tissue was harvested when the tumors were 1-2 cm 3 in size. The metastatic ability of these sublines was determined as described previously [13].…”