Limits...
Lattice-based model of ductal carcinoma in situ suggests rules for breast cancer progression to an invasive state.

Boghaert E, Radisky DC, Nelson CM - PLoS Comput. Biol. (2014)

Bottom Line: We found that the relative rates of cell proliferation and apoptosis governed which of the four morphologies emerged.In agreement with our previous experimental work, we found that cells are more likely to invade from the end of ducts and that this preferential invasion is regulated by cell adhesion and contractility.This model provides additional insight into tumor cell behavior and allows the exploration of phenotypic transitions not easily monitored in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey, United States of America.

ABSTRACT
Ductal carcinoma in situ (DCIS) is a heterogeneous group of non-invasive lesions of the breast that result from abnormal proliferation of mammary epithelial cells. Pathologists characterize DCIS by four tissue morphologies (micropapillary, cribriform, solid, and comedo), but the underlying mechanisms that distinguish the development and progression of these morphologies are not well understood. Here we explored the conditions leading to the emergence of the different morphologies of DCIS using a two-dimensional multi-cell lattice-based model that incorporates cell proliferation, apoptosis, necrosis, adhesion, and contractility. We found that the relative rates of cell proliferation and apoptosis governed which of the four morphologies emerged. High proliferation and low apoptosis favored the emergence of solid and comedo morphologies. In contrast, low proliferation and high apoptosis led to the micropapillary morphology, whereas high proliferation and high apoptosis led to the cribriform morphology. The natural progression between morphologies cannot be investigated in vivo since lesions are usually surgically removed upon detection; however, our model suggests probable transitions between these morphologies during breast cancer progression. Importantly, cribriform and comedo appear to be the ultimate morphologies of DCIS. Motivated by previous experimental studies demonstrating that tumor cells behave differently depending on where they are located within the mammary duct in vivo or in engineered tissues, we examined the effects of tissue geometry on the progression of DCIS. In agreement with our previous experimental work, we found that cells are more likely to invade from the end of ducts and that this preferential invasion is regulated by cell adhesion and contractility. This model provides additional insight into tumor cell behavior and allows the exploration of phenotypic transitions not easily monitored in vivo.

Show MeSH

Related in: MedlinePlus

Generation of morphologies based on number of mitotic events and probability of apoptosis.(A) Varying the probability of apoptosis and the mitosis frequency, we observe the emergence of solid and comedo morphologies at high proliferation rates with low apoptosis and micropapillary morphology at low proliferation rates with high apoptosis. (B) The cribriform morphology emerged occasionally, but not consistently for any of these conditions. Image shown from 1% apoptosis and 25 mitotic events. (C) Schematic of cell division when the division axis is specified to be perpendicular to the epithelial cell layer. Cells shown in pink undergo cell division.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4256017&req=5

pcbi-1003997-g002: Generation of morphologies based on number of mitotic events and probability of apoptosis.(A) Varying the probability of apoptosis and the mitosis frequency, we observe the emergence of solid and comedo morphologies at high proliferation rates with low apoptosis and micropapillary morphology at low proliferation rates with high apoptosis. (B) The cribriform morphology emerged occasionally, but not consistently for any of these conditions. Image shown from 1% apoptosis and 25 mitotic events. (C) Schematic of cell division when the division axis is specified to be perpendicular to the epithelial cell layer. Cells shown in pink undergo cell division.

Mentions: In normal ducts, luminal epithelial cells are polarized and enter a state of growth arrest [46]. Two explanations for this phenomenon have been proposed and validated computationally. In one, normal luminal epithelial cells lose the ability to proliferate when they form tight junctions with their neighbors [47], [48]. In the other, cells continue to proliferate but progeny that enter the lumen subsequently undergo apoptosis [49]. These normal control mechanisms are subverted during DCIS [5]. Here, one quarter of the luminal epithelial cells were chosen randomly and set to proliferate at a given time step, with the axis of cell division perpendicular to the epithelial cell layer (Fig. 2C). In the Results section we discuss the effect of changing the orientation of cell division. We varied the frequency of cell proliferation during the simulation from 10–30 mitotic divisions during 1000 MCS to examine the effects of proliferation on the emergence and progression of DCIS. It has been suggested that cells proliferate more rapidly when located at the outer rim of the lesion [50], [51] which would be expected to alter the pattern of mechanical stresses within the duct; such proliferation patterns have not been widely documented and were not modeled here.


Lattice-based model of ductal carcinoma in situ suggests rules for breast cancer progression to an invasive state.

Boghaert E, Radisky DC, Nelson CM - PLoS Comput. Biol. (2014)

Generation of morphologies based on number of mitotic events and probability of apoptosis.(A) Varying the probability of apoptosis and the mitosis frequency, we observe the emergence of solid and comedo morphologies at high proliferation rates with low apoptosis and micropapillary morphology at low proliferation rates with high apoptosis. (B) The cribriform morphology emerged occasionally, but not consistently for any of these conditions. Image shown from 1% apoptosis and 25 mitotic events. (C) Schematic of cell division when the division axis is specified to be perpendicular to the epithelial cell layer. Cells shown in pink undergo cell division.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4256017&req=5

pcbi-1003997-g002: Generation of morphologies based on number of mitotic events and probability of apoptosis.(A) Varying the probability of apoptosis and the mitosis frequency, we observe the emergence of solid and comedo morphologies at high proliferation rates with low apoptosis and micropapillary morphology at low proliferation rates with high apoptosis. (B) The cribriform morphology emerged occasionally, but not consistently for any of these conditions. Image shown from 1% apoptosis and 25 mitotic events. (C) Schematic of cell division when the division axis is specified to be perpendicular to the epithelial cell layer. Cells shown in pink undergo cell division.
Mentions: In normal ducts, luminal epithelial cells are polarized and enter a state of growth arrest [46]. Two explanations for this phenomenon have been proposed and validated computationally. In one, normal luminal epithelial cells lose the ability to proliferate when they form tight junctions with their neighbors [47], [48]. In the other, cells continue to proliferate but progeny that enter the lumen subsequently undergo apoptosis [49]. These normal control mechanisms are subverted during DCIS [5]. Here, one quarter of the luminal epithelial cells were chosen randomly and set to proliferate at a given time step, with the axis of cell division perpendicular to the epithelial cell layer (Fig. 2C). In the Results section we discuss the effect of changing the orientation of cell division. We varied the frequency of cell proliferation during the simulation from 10–30 mitotic divisions during 1000 MCS to examine the effects of proliferation on the emergence and progression of DCIS. It has been suggested that cells proliferate more rapidly when located at the outer rim of the lesion [50], [51] which would be expected to alter the pattern of mechanical stresses within the duct; such proliferation patterns have not been widely documented and were not modeled here.

Bottom Line: We found that the relative rates of cell proliferation and apoptosis governed which of the four morphologies emerged.In agreement with our previous experimental work, we found that cells are more likely to invade from the end of ducts and that this preferential invasion is regulated by cell adhesion and contractility.This model provides additional insight into tumor cell behavior and allows the exploration of phenotypic transitions not easily monitored in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey, United States of America.

ABSTRACT
Ductal carcinoma in situ (DCIS) is a heterogeneous group of non-invasive lesions of the breast that result from abnormal proliferation of mammary epithelial cells. Pathologists characterize DCIS by four tissue morphologies (micropapillary, cribriform, solid, and comedo), but the underlying mechanisms that distinguish the development and progression of these morphologies are not well understood. Here we explored the conditions leading to the emergence of the different morphologies of DCIS using a two-dimensional multi-cell lattice-based model that incorporates cell proliferation, apoptosis, necrosis, adhesion, and contractility. We found that the relative rates of cell proliferation and apoptosis governed which of the four morphologies emerged. High proliferation and low apoptosis favored the emergence of solid and comedo morphologies. In contrast, low proliferation and high apoptosis led to the micropapillary morphology, whereas high proliferation and high apoptosis led to the cribriform morphology. The natural progression between morphologies cannot be investigated in vivo since lesions are usually surgically removed upon detection; however, our model suggests probable transitions between these morphologies during breast cancer progression. Importantly, cribriform and comedo appear to be the ultimate morphologies of DCIS. Motivated by previous experimental studies demonstrating that tumor cells behave differently depending on where they are located within the mammary duct in vivo or in engineered tissues, we examined the effects of tissue geometry on the progression of DCIS. In agreement with our previous experimental work, we found that cells are more likely to invade from the end of ducts and that this preferential invasion is regulated by cell adhesion and contractility. This model provides additional insight into tumor cell behavior and allows the exploration of phenotypic transitions not easily monitored in vivo.

Show MeSH
Related in: MedlinePlus