Carcinogenesis is thought to originate from a single cell which accumulates a series of well-defined, albeit randomly obtained, genetic mutations, leading to carcinogenic transformation. Despite the inroads into elucidating the carcinogenesis process, there still remain gaps in our understanding of how mutations drive cell transformation and subsequent cancer progression. Although gene mutations clearly contribute to cancer, no single mutated gene or combination of mutated genes occur in all or even the majority of cancers. Moreover, as Vogelstein and Kinzler {Nature Rev Cancer 2004) point out, it is not gene mutations, but primarily chromosome-level aberrations that cells exhibit following transformation to the cancer state. Although it has long been assumed that cancers arise from mutated differentiated cells, mutated stem cells are now also considered candidate cancer precursors due to their self-renewal and differentiation capacity. Although genomic instability is ubiquitous across malignant cancers, its mechanistic underpinnings remain unclear. Inhibition of stability genes, alterations in mitosis genes, aberrant centrosomes, aneuploidy, telomere dysregulations and, for virus-linked cancers, virus-induced fusion of genetically-mutated cells, are all candidate causes of the instability. Given that gene mutations and particularly chromosome aberrations decrease the fitness of a cell, how is it that cancer cell populations are able to sustain and proliferate in the face of the high degree of chromosomal damage per cell? If the answer lies in the existence of cancer stem cells, one needs to ask how this privileged cell compartment is itself exempt from the deleterious effects of chromosomal damage.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA149233-05
Application #
8639493
Study Section
Special Emphasis Panel (ZCA1-SRLB-C)
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$115,074
Indirect Cost
Name
Genesys Research Institute, Inc.
Department
Type
DUNS #
965467512
City
Boston
State
MA
Country
United States
Zip Code
02135
Wilkie, Kathleen P; Hahnfeldt, Philip (2017) Modeling the Dichotomy of the Immune Response to Cancer: Cytotoxic Effects and Tumor-Promoting Inflammation. Bull Math Biol 79:1426-1448
Benzekry, Sebastien; Lamont, Clare; Barbolosi, Dominique et al. (2017) Mathematical Modeling of Tumor-Tumor Distant Interactions Supports a Systemic Control of Tumor Growth. Cancer Res 77:5183-5193
Gao, Xuefeng; Sishc, Brock J; Nelson, Christopher B et al. (2016) Radiation-Induced Reprogramming of Pre-Senescent Mammary Epithelial Cells Enriches Putative CD44(+)/CD24(-/low) Stem Cell Phenotype. Front Oncol 6:138
Beheshti, Afshin; Wage, Justin; McDonald, J Tyson et al. (2015) Tumor-host signaling interaction reveals a systemic, age-dependent splenic immune influence on tumor development. Oncotarget 6:35419-32
Pellicciotta, Ilenia; Marciscano, Ariel E; Hardee, Matthew E et al. (2015) Development of a novel multiplexed assay for quantification of transforming growth factor-? (TGF-?). Growth Factors 33:79-91
Benzekry, Sebastian; Tuszynski, Jack A; Rietman, Edward A et al. (2015) Design principles for cancer therapy guided by changes in complexity of protein-protein interaction networks. Biol Direct 10:32
Beheshti, Afshin; Benzekry, S├ębastien; McDonald, J Tyson et al. (2015) Host age is a systemic regulator of gene expression impacting cancer progression. Cancer Res 75:1134-43
Kareva, Irina; Waxman, David J; Lakka Klement, Giannoula (2015) Metronomic chemotherapy: an attractive alternative to maximum tolerated dose therapy that can activate anti-tumor immunity and minimize therapeutic resistance. Cancer Lett 358:100-6
Poleszczuk, Jan; Hahnfeldt, Philip; Enderling, Heiko (2015) Evolution and phenotypic selection of cancer stem cells. PLoS Comput Biol 11:e1004025
Benzekry, Sebastien; Beheshti, Afshin; Hahnfeldt, Philip et al. (2015) Capturing the Driving Role of Tumor-Host Crosstalk in a Dynamical Model of Tumor Growth. Bio Protoc 5:

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