Advanced Intestinal Cancers often Maintain a Multi-Ancestral Architecture.

Zahm CD, Szulczewski JM, Leystra AA, Paul Olson TJ, Clipson L, Albrecht DM, Middlebrooks M, Thliveris AT, Matkowskyj KA, Washington MK, Newton MA, Eliceiri KW, Halberg RB
PLoS One. 2016 11 (2): e0150170

PMID: 26919712 · PMCID: PMC4769224 · DOI:10.1371/journal.pone.0150170

A widely accepted paradigm in the field of cancer biology is that solid tumors are uni-ancestral being derived from a single founder and its descendants. However, data have been steadily accruing that indicate early tumors in mice and humans can have a multi-ancestral origin in which an initiated primogenitor facilitates the transformation of neighboring co-genitors. We developed a new mouse model that permits the determination of clonal architecture of intestinal tumors in vivo and ex vivo, have validated this model, and then used it to assess the clonal architecture of adenomas, intramucosal carcinomas, and invasive adenocarcinomas of the intestine. The percentage of multi-ancestral tumors did not significantly change as tumors progressed from adenomas with low-grade dysplasia [40/65 (62%)], to adenomas with high-grade dysplasia [21/37 (57%)], to intramucosal carcinomas [10/23 (43%]), to invasive adenocarcinomas [13/19 (68%)], indicating that the clone arising from the primogenitor continues to coexist with clones arising from co-genitors. Moreover, neoplastic cells from distinct clones within a multi-ancestral adenocarcinoma have even been observed to simultaneously invade into the underlying musculature [2/15 (13%)]. Thus, intratumoral heterogeneity arising early in tumor formation persists throughout tumorigenesis.

MeSH Terms (30)

Adenocarcinoma Adenoma Animals Carcinoma in Situ Cell Lineage Cell Transformation, Neoplastic Clone Cells Disease Models, Animal Disease Progression Evolution, Molecular Fatty Acid-Binding Proteins Female Gene Expression Regulation, Neoplastic Genes, APC Genes, Reporter Integrases Intestinal Mucosa Intestinal Neoplasms Luminescent Proteins Male Mice Mice, Inbred C57BL Models, Biological Mosaicism Neoplasm Invasiveness Neoplastic Stem Cells Rats RNA, Untranslated Transgenes Tumor Microenvironment

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