Heterogeneity of MHC-class-I antigens in clones of methylcholanthrene-induced tumors. Implications for local growth and metastasis.

We analyzed the H-2 class-I expression of different clones obtained from 4 different methylcholanthrene-induced tumors in BALB/c (H-2d) mice. The results clearly indicated high intra-tumor heterogeneity in all 4 fibrosarcomas with regard to H-2 K, D and L expression. Clones were found to be H-2-negative, H-2-positive, or to present intermediate expression. Southern blot analysis of class-I genes showed RFLPs equal to those obtained from normal BALB/c DNA, ruling out rearrangements or gross deletions in the class-I genes of different tumors. However, Northern blot studies showed a straightforward relationship between class-I mRNA levels and H-2 expression. In vivo experiments demonstrated an inverse relationship between local growth and spontaneous metastasis, e.g., H-2-positive class-I clones produced high numbers of lung colonies but very poor local growth, and vice-versa. These results paralleled the NK sensitivity or resistance of the different clones. Cross-protection experiments showed that only clones coming from the same tumor were able to protect against challenge with clones of the same neoplasia but not with clones from different chemically induced fibrosarcomas, indicating that a clone of a given tumor probably contained the same TATA. Finally, we compared the H-2, K, D and L expression and class-I mRNA levels of various metastatic colonies. Interestingly, another degree of heterogeneity was found: an H-2-negative clone (GR9.B9) gave rise to H-2-negative (B9MP6) and H-2-positive (B9MP2) metastatic colonies.