Microbiota does not influence tumor development in two models of heritable cancer

Abstract

Microbial impact on tumorigenesis of heritable cancers proximal to the gut is well-documented. Whether the microbiota influences cancers arising from inborn mutations at sites distal to the gut is undetermined. Using two models of heritable cancer, Trp53-deficient mice and Wnt1-transgenic mice, and a gnotobiotic approach, we found the microbiota to be inconsequential for tumor development. This work furthers our understanding of the degree of the microbial impact on tumor development.

Importance: The influence of the microbiome on the development of cancer is well-documented with many if not all published studies reporting either a positive or a negative impact. None of the published studies, however, presented data on the influence of the microbiome on the development of heritable cancer. We find that the microbiota has no influence on cancer development in two models of spontaneous cancers driven by germline Trp53 deficiency and constitutive Wnt1 signaling.

Keywords: cancer; genetic predisposition to cancer; gut commensal bacteria; heritable cancer; microbiota.

Fig 1

Microbiota does not impact the latency and incidence of tumor development in Trp53^−/− mice. (A) Trp53^−/− SPF and GF mice were monitored for tumor development. (B) Proportion of SPF Trp53^−/− mice that develop various forms of tumors in SPF (left) and GF (right) mice. n, number of mice used. Of 26 SPF Trp53^−/− mice, 15 were males and 11 were females, whereas of 41 GF Trp53^−/− mice, 30 were males and 21 were females. Twenty of 26 SPF tumors were histologically analyzed. Of those, 14 were identified as lymphomas and six as sarcomas. Of 41 GF tumors, 27 were histologically analyzed. Of those, 21 were identified as lymphomas, five as sarcomas, and one as carcinoma. P values calculated using Mantel-Cox test (A).

Fig 2

The microbiota does not influence the latency and incidence of tumor development in Wnt1-transgenic mice. (A) Virgin Wnt1-transgenic SPF and GF females were monitored for tumor development. (B) Proportion of Wnt1-transgenic mice that develop various types of tumors in SPF (left) and GF (right) mice. n, number of mice used. Seventeen of 27 SPF tumors were histologically analyzed and identified as adenocarcinomas. Fifteen of 22 GF tumors were histologically analyzed, 14 were identified as adenocarcinomas, and one as carcinoma. P values calculated using Mantel-Cox test (A).

Fig 3

Intrinsic dissimilarities between spontaneous (virally induced) and heritable tumors which could explain differential dependence on the microbiota. (A) Virally induced tumors, such as MuLV-induced leukemia are initiated from rare cells with proviral integration next to the cellular proto-oncogene (“first hit” mutation, shown as red X). In MuLV-infected germ-free (GF) mice, viral antigens expressed by precancerous cells stimulate a strong immune response suppressing leukemia development (acquisition of additional mutations required for tumor progression). In MuLV-infected specific pathogen-free (SPF) mice, commensal bacteria suppress the immune response against viral antigens enabling acquisition of additional mutations (shown as green and blue XX) and progression to leukemia. Data shown in the figure are from reference . (B) The “first hit” mutation in heritable cancer is present since birth. Self-antigens expressed in excess by tumor cells may cause either immunological ignorance or immune suppression leading to tumor development regardless of the presence of the microbiota. DC, dendritic cell; Treg, T regulatory cell.