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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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Progression between DCIS morphologies.(A) With no apoptosis and high proliferation (mitosis every 65 MCS, 15 mitotic events over 1000 MCS) we observe transitions from micropapillary to solid morphology and from solid to comedo morphology. Cell division axis was specified perpendicular to the epithelial layer. (B) With high apoptosis (1% probability) and high proliferation (mitosis every 38 MCS, 25 mitotic events over 1000 MCS) we observe transitions from the micropapillary to the cribriform morphology. Cell division axis was specified parallel to the epithelial layer. (C) With low apoptosis (0.5% probability) or (D) high apoptosis (1% probability) and low proliferation (mitosis every 65 MCS, 15 mitotic events over 1000 MCS) we observe only the micropapillary morphology. Cell division axis was random. LEP are capable of invading through the MEP layer from (E) micropapillary, (F) cribriform, (G) solid, and (H) comedo morphologies. The images shown here were generated under the following conditions: (E and F) 1% probability of apoptosis, mitosis every 32 MCS (30 mitotic events over 1000 MCS), and cell division axis parallel to the epithelial layer; (G) 0.5% probability of apoptosis, mitosis every 32 MCS (30 mitotic events over 1000 MCS), and random cell division axis; (H) 0.5% probability of apoptosis, mitosis every 38 MCS (25 mitotic events over 1000 MCS), and cell division axis parallel to the epithelial layer.
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pcbi-1003997-g004: Progression between DCIS morphologies.(A) With no apoptosis and high proliferation (mitosis every 65 MCS, 15 mitotic events over 1000 MCS) we observe transitions from micropapillary to solid morphology and from solid to comedo morphology. Cell division axis was specified perpendicular to the epithelial layer. (B) With high apoptosis (1% probability) and high proliferation (mitosis every 38 MCS, 25 mitotic events over 1000 MCS) we observe transitions from the micropapillary to the cribriform morphology. Cell division axis was specified parallel to the epithelial layer. (C) With low apoptosis (0.5% probability) or (D) high apoptosis (1% probability) and low proliferation (mitosis every 65 MCS, 15 mitotic events over 1000 MCS) we observe only the micropapillary morphology. Cell division axis was random. LEP are capable of invading through the MEP layer from (E) micropapillary, (F) cribriform, (G) solid, and (H) comedo morphologies. The images shown here were generated under the following conditions: (E and F) 1% probability of apoptosis, mitosis every 32 MCS (30 mitotic events over 1000 MCS), and cell division axis parallel to the epithelial layer; (G) 0.5% probability of apoptosis, mitosis every 32 MCS (30 mitotic events over 1000 MCS), and random cell division axis; (H) 0.5% probability of apoptosis, mitosis every 38 MCS (25 mitotic events over 1000 MCS), and cell division axis parallel to the epithelial layer.

Mentions: Whereas it is difficult to explore the transitions between DCIS morphologies in intact tumors in vivo, this is readily achieved in silico. Examining intermediate time steps and running simulations for up to 3000 MCS, we observed multiple transitions between morphologies. As LEP accumulated in the lumen, the micropapillary morphology was the first to emerge. In the absence of apoptosis, or at low levels of apoptosis (0.5% probability) with high proliferation, the micropapillary morphology progressed to solid and ultimately to comedo as the force of proliferating cells caused the duct to expand outward (Fig. 4A). At higher levels of apoptosis (1% probability) and high levels of proliferation, the micropapillary morphology progressed to cribriform (Fig. 4B). With low levels of proliferation, the morphology remained micropapillary (Fig. 4C, D). Increasing apoptosis from 0.5% probability to 1% probability did not affect the outcome of these simulations. Notably, high levels of apoptosis or low levels of apoptosis balancing low levels of proliferation caused the duct to remain fairly uniform in size (Fig. 4B–D). Given that the cells continued to proliferate, we had anticipated that the lumen would fill completely and the cribriform morphology would ultimately progress to a solid morphology. Surprisingly, however, the morphology remained cribriform even after 3000 MCS under conditions of 1% probability of apoptosis and high proliferation (Fig. 4B). This suggests that over longer periods of time, comedo and cribriform may be the ultimate morphological outcomes of DCIS, with apoptosis being the deciding factor. Importantly, we found that LEP were able to break through the MEP layer into the surroundings from any of the four morphologies (Fig. 4E–H). For our purposes here we refer to this phenotype as invasion; however, we note that physiological invasion in vivo requires deterioration of the basement membrane, which is not included in the present model.


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)

Progression between DCIS morphologies.(A) With no apoptosis and high proliferation (mitosis every 65 MCS, 15 mitotic events over 1000 MCS) we observe transitions from micropapillary to solid morphology and from solid to comedo morphology. Cell division axis was specified perpendicular to the epithelial layer. (B) With high apoptosis (1% probability) and high proliferation (mitosis every 38 MCS, 25 mitotic events over 1000 MCS) we observe transitions from the micropapillary to the cribriform morphology. Cell division axis was specified parallel to the epithelial layer. (C) With low apoptosis (0.5% probability) or (D) high apoptosis (1% probability) and low proliferation (mitosis every 65 MCS, 15 mitotic events over 1000 MCS) we observe only the micropapillary morphology. Cell division axis was random. LEP are capable of invading through the MEP layer from (E) micropapillary, (F) cribriform, (G) solid, and (H) comedo morphologies. The images shown here were generated under the following conditions: (E and F) 1% probability of apoptosis, mitosis every 32 MCS (30 mitotic events over 1000 MCS), and cell division axis parallel to the epithelial layer; (G) 0.5% probability of apoptosis, mitosis every 32 MCS (30 mitotic events over 1000 MCS), and random cell division axis; (H) 0.5% probability of apoptosis, mitosis every 38 MCS (25 mitotic events over 1000 MCS), and cell division axis parallel to the epithelial layer.
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getmorefigures.php?uid=PMC4256017&req=5

pcbi-1003997-g004: Progression between DCIS morphologies.(A) With no apoptosis and high proliferation (mitosis every 65 MCS, 15 mitotic events over 1000 MCS) we observe transitions from micropapillary to solid morphology and from solid to comedo morphology. Cell division axis was specified perpendicular to the epithelial layer. (B) With high apoptosis (1% probability) and high proliferation (mitosis every 38 MCS, 25 mitotic events over 1000 MCS) we observe transitions from the micropapillary to the cribriform morphology. Cell division axis was specified parallel to the epithelial layer. (C) With low apoptosis (0.5% probability) or (D) high apoptosis (1% probability) and low proliferation (mitosis every 65 MCS, 15 mitotic events over 1000 MCS) we observe only the micropapillary morphology. Cell division axis was random. LEP are capable of invading through the MEP layer from (E) micropapillary, (F) cribriform, (G) solid, and (H) comedo morphologies. The images shown here were generated under the following conditions: (E and F) 1% probability of apoptosis, mitosis every 32 MCS (30 mitotic events over 1000 MCS), and cell division axis parallel to the epithelial layer; (G) 0.5% probability of apoptosis, mitosis every 32 MCS (30 mitotic events over 1000 MCS), and random cell division axis; (H) 0.5% probability of apoptosis, mitosis every 38 MCS (25 mitotic events over 1000 MCS), and cell division axis parallel to the epithelial layer.
Mentions: Whereas it is difficult to explore the transitions between DCIS morphologies in intact tumors in vivo, this is readily achieved in silico. Examining intermediate time steps and running simulations for up to 3000 MCS, we observed multiple transitions between morphologies. As LEP accumulated in the lumen, the micropapillary morphology was the first to emerge. In the absence of apoptosis, or at low levels of apoptosis (0.5% probability) with high proliferation, the micropapillary morphology progressed to solid and ultimately to comedo as the force of proliferating cells caused the duct to expand outward (Fig. 4A). At higher levels of apoptosis (1% probability) and high levels of proliferation, the micropapillary morphology progressed to cribriform (Fig. 4B). With low levels of proliferation, the morphology remained micropapillary (Fig. 4C, D). Increasing apoptosis from 0.5% probability to 1% probability did not affect the outcome of these simulations. Notably, high levels of apoptosis or low levels of apoptosis balancing low levels of proliferation caused the duct to remain fairly uniform in size (Fig. 4B–D). Given that the cells continued to proliferate, we had anticipated that the lumen would fill completely and the cribriform morphology would ultimately progress to a solid morphology. Surprisingly, however, the morphology remained cribriform even after 3000 MCS under conditions of 1% probability of apoptosis and high proliferation (Fig. 4B). This suggests that over longer periods of time, comedo and cribriform may be the ultimate morphological outcomes of DCIS, with apoptosis being the deciding factor. Importantly, we found that LEP were able to break through the MEP layer into the surroundings from any of the four morphologies (Fig. 4E–H). For our purposes here we refer to this phenotype as invasion; however, we note that physiological invasion in vivo requires deterioration of the basement membrane, which is not included in the present model.

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