Malignant cancer and invasive placentation: A case for positive pleiotropy between endometrial and malignancy phenotypes

Abstract

Cancer metastasis is an invasive process that involves the transplantation of cells into new environments. Since human placentation is also invasive, hypotheses about a relationship between invasive placentation in eutherian mammals and metastasis have been proposed. The relationship between metastatic cancer and invasive placentation is usually presented in terms of antagonistic pleiotropy. According to this hypothesis, evolution of invasive placentation also established the mechanisms for cancer metastasis. Here, in contrast, we argue that the secondary evolution of less invasive placentation in some mammalian lineages may have resulted in positive pleiotropic effects on cancer survival by lowering malignancy rates. These positive pleiotropic effects would manifest themselves as resistance to cancer cell invasion. To provide a preliminary test of this proposal, we re-analyze data from Priester and Mantel (Occurrence of tumors in domestic animals. Data from 12 United States and Canadian colleges of veterinary medicine. J Natl Cancer Inst 1971; 47: :1333-44) about malignancy rates in cows, horses, cats and dogs. From our analysis we found that equines and bovines, animals with less invasive placentation, have lower rates of metastatic cancer than felines and canines in skin and glandular epithelial cancers as well as connective tissue sarcomas. We conclude that a link between type of placentation and species-specific malignancy rates is more likely related to derived mechanisms that suppress invasion rather than different degrees of fetal placental aggressiveness.

Keywords: antagonistic pleiotropy; cancer; evolution of malignancy; evolution of placentation.

Figure 1.

Two models for the relationship between placental invasiveness and malignancy. (A) The antagonistic pleiotropy model assumes that malignancy is a deleterious side effect of the evolution of invasive placentation. This model is supported by the similarity of the molecular mechanisms involved in trophoblast invasion and cancer invasion (metastasis). (B) The positive pleiotropy model assumes that the secondary loss of invasive placentation in some lineages of eutherian mammals is due to a derived maternal response to embryo attachment suppressing trophoblast invasion. These mechanisms are hypothesized to have a protective effect against invasiveness from cancers. M = metastatic cancer, NM = non-metastatic cancer, E = epitheliochorial placentation, H = hemochorial placentation, SE = secondarily epitheliochorial placentation

Figure 2.

Percentage of tumors for each anatomic site and animal from Priester and Mantel [8]. The colored bars indicate significance values of pairwise Fisher’s exact tests. Gray is non-significant, black is P < 0.05, orange is P < 0.005 and red is P < 0.0001. Note that there are two patterns, one with uniformly high malignancy rates for non-glandular epithelial cancers, and one for the other categories of cancers. In the latter case the hoofed animals, which have non-invasive placentation, have lower malignancy rates than carnivores that have an invasive form of placentation