Melanoma with Inhibition of the Desmoplastic Response in C57 Increased Invasion and Spontaneous Metastasis of BL6

BL6 melanoma cells injected s.c. in 18-month C57 BL/6 mice elicit a markedly fibrotic response similar in myofibroblast and collagen com position to that characterizing the desmoplastic response of human breast carcinoma. This host response can be quantitated by measuring hydroxyproline (total collagen) and incorporation of i.p.-injected [uC]proline into collagenase-sensitive protein (new collagen synthesis). Inhibition (70%) of the desmoplastic response can be achieved by daily injections of i.-3,4-dehydroproline. Inhibiting the response in this manner promotes local invasion of tumor and increases the incidence of spontaneous pulmonary metastasis. 10' HI .<>melanoma cells produce tumor nodules with a mean diameter of 1.5 ±0.5 cm and mean collagen content of 36 ±15 mg/g wet tissue at 4 weeks and 10% incidence of pulmonary metastasis at 7 weeks. l.-3,4-dehydroproline produces nodules with a mean diameter of 2.3 ±0.5 cm and mean collagen content of 12 ±2 mg/ g with a 40% incidence of metastasis. L-3,4-dehydroproline exerts a selective effect on myofibroblast collagen synthesis in vitro and no effect on |'Il|(h\uiiiliiuuptake, doubling time, and viability of BL6 cells and myofibroblasts. Furthermore, this drug exerts no effect on HI,6 invasion and metastasis in 6-week C57 BL/6 mice, hosts which exhibit a negligible desmoplastic response.