MSH3-deficiency initiates EMAST without oncogenic transformation of human colon epithelial cells.

Background/aim: Elevated microsatellite instability at selected tetranucleotide repeats (EMAST) is a genetic signature in certain cases of sporadic colorectal cancer and has been linked to MSH3-deficiency. It is currently controversial whether EMAST is associated with oncogenic properties in humans, specifically as cancer development in Msh3-deficient mice is not enhanced. However, a mutator phenotype is different between species as the genetic positions of repetitive sequences are not conserved.

Toll-like receptor 4 variant D299G induces features of neoplastic progression in Caco-2 intestinal cells and is associated with advanced human colon cancer.

Background & Aims: The Toll-like receptor (TLR) 4 mediates homeostasis of the intestinal epithelial cell (IEC) barrier. We investigated the effects of TLR4-D299G on IEC functions.

Methods: We engineered IECs (Caco-2) to stably overexpress hemagglutinin-tagged wild-type TLR4, TLR4-D299G, or TLR4-T399I.

Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice.

The nuclear receptor pregnane X receptor (PXR) is activated by a range of xenochemicals, including chemotherapeutic drugs, and has been suggested to play a role in the development of tumor cell resistance to anticancer drugs. PXR also has been implicated as a regulator of the growth and apoptosis of colon tumors. Here, we have used a xenograft model of colon cancer to define a molecular mechanism that might underlie PXR-driven colon tumor growth and malignancy.

Functional parsing of driver mutations in the colorectal cancer genome reveals numerous suppressors of anchorage-independent growth.

Landmark cancer genome resequencing efforts are leading to the identification of mutated genes in many types of cancer. The extreme diversity of mutations being detected presents significant challenges to subdivide causal from coincidental mutations to elucidate how disrupted regulatory networks drive cancer processes. Given that a common early perturbation in solid tumor initiation is bypass of matrix-dependent proliferation restraints, we sought to functionally interrogate colorectal cancer candidate genes (CAN-genes) to identify driver tumor suppressors.

Characterization of aneuploid populations with trisomy 7 and 20 derived from diploid human colonic epithelial cells.

Chromosomal instability leading to aneuploidy occurs in most sporadic colorectal cancers (CRCs) and is believed to be an early driving force in disease progression. Despite this observation, the cellular advantages conferred by these cytogenetic alterations are poorly understood. Here, we provide evidence that serum-free passage of originally diploid, immortalized human colonic epithelial cells (HCECs) gave rise to the acquisition of trisomy 7 (+7), an aneuploidy detected in more than 40% of colorectal adenomas.

CDDO-Me protects against space radiation-induced transformation of human colon epithelial cells.

Radiation-induced carcinogenesis is a major concern both for astronauts on long-term space missions and for cancer patients being treated with therapeutic radiation. Exposure to radiation induces oxidative stress and chronic inflammation, which are critical initiators and promoters of carcinogenesis. Many studies have demonstrated that non-steroidal anti-inflammatory drugs and antioxidants can reduce the risk of radiation-induced cancer.

DNA damage intensity in fibroblasts in a 3-dimensional collagen matrix correlates with the Bragg curve energy distribution of a high LET particle.

Purpose: The DNA double-strand break (DSB) damage response induced by high energy charged particles on lung fibroblast cells embedded in a 3-dimensional (3-D) collagen tissue equivalents was investigated using antibodies to the DNA damage response proteins gamma-histone 2AX (gamma-H2AX) and phosphorylated DNA-PKcs (p-DNA-PKcs).

Materials And Methods: 3-D tissue equivalents were irradiated in positions across the linear distribution of the Bragg curve profiles of 307.7 MeV/nucleon, 556.

Immortalized epithelial cells derived from human colon biopsies express stem cell markers and differentiate in vitro.

Background & Aims: Long-term propagation of human colonic epithelial cells (HCEC) of adult origin has been a challenge; currently used HCEC lines are of malignant origin and/or contain multiple cytogenetic changes. We sought to immortalize human colon biopsy-derived cells expressing stem cell markers and retaining multilineage epithelial differentiation capability.

Methods: We isolated and cultured cells from biopsy samples of 2 patients undergoing routine screening colonoscopy.

Two- and three-dimensional models for risk assessment of radiation-enhanced colorectal tumorigenesis.

Astronauts may be at an increased risk for developing colorectal cancer after a prolonged interplanetary mission given the potential for greater carcinogenic effects of radiation to the colon. In addition, with an increase in age, there is a greater incidence of premalignant colon adenomas with age. In the present study, we have compared the effects of radiation on human colon epithelial cells in two-dimensional (2D) monolayer culture, in three-dimensional (3D) culture, and in intact human colon tissue biopsies.