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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.

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Cells invade preferentially from the ends of bifurcating ducts.(A) In control tissues cells invade preferentially from the ends of bifurcating ducts. Decreasing contractility partially inhibits invasion, while increasing contractility causes delocalization of invasion. (B) Quantification of tissues with invasion at the end and the duct region of each tissue at 3000 MCS. Simulations were run with high proliferation (mitosis every 65 MCS) and high apoptosis (1% probability), 20 times for each of the parameters described in Fig. 6F–G.
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pcbi-1003997-g007: Cells invade preferentially from the ends of bifurcating ducts.(A) In control tissues cells invade preferentially from the ends of bifurcating ducts. Decreasing contractility partially inhibits invasion, while increasing contractility causes delocalization of invasion. (B) Quantification of tissues with invasion at the end and the duct region of each tissue at 3000 MCS. Simulations were run with high proliferation (mitosis every 65 MCS) and high apoptosis (1% probability), 20 times for each of the parameters described in Fig. 6F–G.

Mentions: We previously used a transgenic mouse expressing an inducible form of the kRas oncogene under control of the mouse mammary tumor virus (MMTV) promoter to observe tumor development in vivo in the post-pubertal mammary gland. These studies revealed that tumors form more frequently at the ends of the complex network of epithelial ducts in adult mice [25]. We thus expanded our computational model to examine tumor growth in a bifurcating duct, and observed that tumor cells invaded more often from the ends of the bifurcating duct. Using the same parameters for low and high contractility described above and presented in Fig. 6, we explored the effect of altering tissue contractility. Low contractility caused the morphology to remain micropapillary, whereas high contractility led to the development of a cribriform morphology with necrotic cells in the center of the tissue (Fig. 7A). Again we found that invasion was reduced by decreasing contractility and delocalized by increasing contractility (Fig. 7). Agreement between these in vivo and computational results suggests that this model could be expanded to predict tumor cell behavior in increasingly complex physiologically relevant geometries.


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)

Cells invade preferentially from the ends of bifurcating ducts.(A) In control tissues cells invade preferentially from the ends of bifurcating ducts. Decreasing contractility partially inhibits invasion, while increasing contractility causes delocalization of invasion. (B) Quantification of tissues with invasion at the end and the duct region of each tissue at 3000 MCS. Simulations were run with high proliferation (mitosis every 65 MCS) and high apoptosis (1% probability), 20 times for each of the parameters described in Fig. 6F–G.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003997-g007: Cells invade preferentially from the ends of bifurcating ducts.(A) In control tissues cells invade preferentially from the ends of bifurcating ducts. Decreasing contractility partially inhibits invasion, while increasing contractility causes delocalization of invasion. (B) Quantification of tissues with invasion at the end and the duct region of each tissue at 3000 MCS. Simulations were run with high proliferation (mitosis every 65 MCS) and high apoptosis (1% probability), 20 times for each of the parameters described in Fig. 6F–G.
Mentions: We previously used a transgenic mouse expressing an inducible form of the kRas oncogene under control of the mouse mammary tumor virus (MMTV) promoter to observe tumor development in vivo in the post-pubertal mammary gland. These studies revealed that tumors form more frequently at the ends of the complex network of epithelial ducts in adult mice [25]. We thus expanded our computational model to examine tumor growth in a bifurcating duct, and observed that tumor cells invaded more often from the ends of the bifurcating duct. Using the same parameters for low and high contractility described above and presented in Fig. 6, we explored the effect of altering tissue contractility. Low contractility caused the morphology to remain micropapillary, whereas high contractility led to the development of a cribriform morphology with necrotic cells in the center of the tissue (Fig. 7A). Again we found that invasion was reduced by decreasing contractility and delocalized by increasing contractility (Fig. 7). Agreement between these in vivo and computational results suggests that this model could be expanded to predict tumor cell behavior in increasingly complex physiologically relevant geometries.

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