As cancer grows old.

Mutations trace the evolution of an ancient tumor lineage.

Transient downregulation of monocyte-derived dendritic-cell differentiation, function, and survival during tumoral progression and regression in an in vivo canine model of transmissible venereal tumor.

Tumors often target dendritic cells (DCs) to evade host immune surveillance. DC injury is reported in many rodent and human tumors but seldom in tumors of other mammals. Canine transmissible venereal tumor (CTVT), a unique and spontaneous cancer transmitted by means of viable tumor cells. CTVT causes manifold damage to monocyte-derived DCs. This cancer provides an in vivo model of cancer to study the role of monocyte-derived DCs during spontaneous regression. Using flow cytometry and real-time reverse-transcription polymerase chain reactions, we compared the expression of surface molecules on monocyte-derived DCs between normal dogs and dogs with CTVT. These markers were CD1a, CD83, costimulatory factors (CD40, CD80, and CD86), and major histocompatability complex classes I and II. In immature DCs (iDCs) and lipopolysaccharide-treated mature DCs (mDCs), the surface markers were mostly downregulated during tumoral progression and regression. The tumor lowered endocytic activity of iDCs, as reflected in dextran uptake, and decreased allogeneic mixed lymphocyte reactions of mDCs. In addition, it decreased the number of monocytes in the peripheral blood by 40%. The tumor substantially impaired the efficiency with which DCs were generated from monocytes and with which mDCs were generated from iDCs. We also found that progression-phase CTVT supernatants that were cultured for 48 h and that contained protein components killed both monocytes and DCs. Additionally, DC numbers were significantly lower in the draining lymph nodes in CTVT dogs than in normal dogs. In conclusion, CTVT caused devastating damage to monocyte-derived DCs; this might be one of its mechanisms for evading host immunity. Reestablishment of monocyte-derived DC activity by the host potentially might contribute to spontaneous tumoral regression. These findings provide insight into the extent of tumoral effects on host immune systems and responses. This information is useful for developing cancer immunotherapies.

The singular history of a canine transmissible tumor.

In this issue of Cell, Murgia et al. (2006) confirm that the infectious agent of canine transmissible venereal tumor is the cancer cell itself and that the tumor is clonal in origin. Their findings have implications for understanding the relationship between genome instability and transmissible cancer and for conservation biology, canine genomics, and companion animal medicine.

Semen quality during vincristine treatment in dogs with transmissible venereal tumor.

The aim of this study was to evaluate the direct effects of vincristine on semen quality in dogs with transmissible venereal tumor (TVT). We examined the semen of 17 dogs suffering from TVT during vincristine treatment. Each animal received 0.6 mg, i.v. vincristine sulphate per square meter of body surface, per week for 4 wk until complete regression of the tumor. The following semen parameters were evaluated: semen volume (second fraction), sperm concentration, total spermatozoa per ejaculate, percentage of progressively motile spermatozoa, percentage of dead spermatozoa, percentage of swollen spermatozoa (hypo-osmotic swelling test) and percentage of morphologically abnormal spermatozoa (primary and secondary defects). Semen was collected and evaluated prior to the beginning of treatment, 3 d after each vincristine injection and 15 d after the last injection. Semen characteristics transiently deteriorated during treatment, but returned to normal 15 d later. These changes were attributed to a direct effect of vincristine on the extragonadal spermatozoal reserves contained in the epididymis and ductus deferens. A GnRH stimulation test was also performed after each semen collection in order to assess the function of the hypothalamic-pituitary-Leydig cell axis. No effect was noted on the above axis.

Hydralazine-enhanced selective heating of transmissible venereal tumor implants in dogs.

This study was designed to test the hypothesis that vasodilator drugs can enhance selective heating of solid tumors by producing a favorable redistribution of blood flow between tumor and normal tissues. Subcutaneous transmissible venereal tumor implants were heated by inductive diathermy using Helmholtz coils in 8 dogs. The temperature rise in tumor and adjacent muscle was measured before and after giving hydralazine (0.5 mg/kg i.v.). Blood flow to the tumors and underlying muscle was measured with radioactive tracer microspheres. Before hydralazine treatment mean muscle blood flow was about one-third tumor blood flow (0.11 +/- 0.02 vs 0.28 +/- 0.09 ml/min/g), and tumor and normal muscle temperatures were not significantly different (40.0 +/- 0.6 vs 39.7 +/- 0.1 degrees C). After hydralazine tumor blood flow decreased and muscle blood flow increased in every dog, and selective heating of the tumors became possible. Muscle blood flow averaged 0.67 +/- 0.13 ml/min/g, 17 times greater than tumor blood flow, which decreased to 0.04 +/- 0.02 ml/min/g. Core tumor temperature was 48.0 +/- 0.9 vs 38.5 +/- 0.5 degrees C for underlying muscle. Blood pressure was maintained at 80 +/- 5.7 mmHg. These results demonstrate that adjuvant treatment with vasodilators is a promising technique to increase the temperature difference between tumors and surrounding normal tissues during local heat therapy.