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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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Varying cell division axis leads to increased development of multiple lumena.Schematic of cell division with the cell division axis specified to be parallel to the epithelial cell layer (A) or random (C). Cells shown in pink undergo cell division. Varying the probability of apoptosis and mitosis frequency, we observe an increased emergence of multiple lumena when the cell division axis is parallel to the epithelial cell layer (B) or chosen randomly (D).
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pcbi-1003997-g003: Varying cell division axis leads to increased development of multiple lumena.Schematic of cell division with the cell division axis specified to be parallel to the epithelial cell layer (A) or random (C). Cells shown in pink undergo cell division. Varying the probability of apoptosis and mitosis frequency, we observe an increased emergence of multiple lumena when the cell division axis is parallel to the epithelial cell layer (B) or chosen randomly (D).

Mentions: As described above, there are two possible mechanisms by which cells in a normal duct can undergo growth arrest. In one, normal 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 any daughter progeny that occupy the lumen immediately undergo apoptosis [49]. Thus, we next explored how the axis of cell division affects the morphology of the simulated duct. In the simulations described above (Fig. 2), we had specified the axis of cell division to be perpendicular to the epithelial cell layer (Fig. 2C); next we investigated the effects of cell divisions that introduced progeny into the lumen which were protected from undergoing apoptosis (0% probability; Fig. 3A, B), or allowing the cells to undergo random cell division thereby resulting in a loss of tissue polarity (Fig. 3C, D). Regardless of the axis of cell division, solid and comedo morphologies were established under combinations of high proliferation (25 or more mitotic events) and low apoptosis (0.5% probability). When the cell division axis was random or such that daughter cells were placed into the lumen, the duct appeared to expand slightly more than when the division axis was perpendicular to the epithelial cell layer. The former caused a small lumen to appear in conditions that otherwise led to a solid morphology (compare Fig. 2A solid morphology to Fig. 3B solid morphology). For example, with 0.5% apoptosis and 25 mitotic events, the duct became almost completely filled with LEP; however, in half of the simulations a very small lumen remained.


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)

Varying cell division axis leads to increased development of multiple lumena.Schematic of cell division with the cell division axis specified to be parallel to the epithelial cell layer (A) or random (C). Cells shown in pink undergo cell division. Varying the probability of apoptosis and mitosis frequency, we observe an increased emergence of multiple lumena when the cell division axis is parallel to the epithelial cell layer (B) or chosen randomly (D).
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003997-g003: Varying cell division axis leads to increased development of multiple lumena.Schematic of cell division with the cell division axis specified to be parallel to the epithelial cell layer (A) or random (C). Cells shown in pink undergo cell division. Varying the probability of apoptosis and mitosis frequency, we observe an increased emergence of multiple lumena when the cell division axis is parallel to the epithelial cell layer (B) or chosen randomly (D).
Mentions: As described above, there are two possible mechanisms by which cells in a normal duct can undergo growth arrest. In one, normal 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 any daughter progeny that occupy the lumen immediately undergo apoptosis [49]. Thus, we next explored how the axis of cell division affects the morphology of the simulated duct. In the simulations described above (Fig. 2), we had specified the axis of cell division to be perpendicular to the epithelial cell layer (Fig. 2C); next we investigated the effects of cell divisions that introduced progeny into the lumen which were protected from undergoing apoptosis (0% probability; Fig. 3A, B), or allowing the cells to undergo random cell division thereby resulting in a loss of tissue polarity (Fig. 3C, D). Regardless of the axis of cell division, solid and comedo morphologies were established under combinations of high proliferation (25 or more mitotic events) and low apoptosis (0.5% probability). When the cell division axis was random or such that daughter cells were placed into the lumen, the duct appeared to expand slightly more than when the division axis was perpendicular to the epithelial cell layer. The former caused a small lumen to appear in conditions that otherwise led to a solid morphology (compare Fig. 2A solid morphology to Fig. 3B solid morphology). For example, with 0.5% apoptosis and 25 mitotic events, the duct became almost completely filled with LEP; however, in half of the simulations a very small lumen remained.

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