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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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Patterns of cell invasion depend on cell adhesion and contractility.In the absence of proliferation, changing the adhesion parameter and the focal point plasticity parameter does not significantly alter tissue structure. (A) Images were generated using JLEP,LEP, JMEP,LEP, and JMEP,MEP values of −2, −1, −0.5; −10, −5, −2.5; −20, −10, −5; −40, −20, −10; and −100, −50, −25 with FPPP set to zero. (B) Images were generated using FPP parameters of 5 and 0.5, 25 and 2.5, 50 and 5, 75 and 7.5, and 100 and 10 for homotypic and heterotypic interactions, respectively. With high proliferation (mitosis every 65 MCS) and high apoptosis (1% probability), changing the adhesion parameter and the focal point plasticity parameter affects cell invasion. (C) When cell adhesion is decreased cells invade from the entire periphery of the tissue. Adhesion and FPP parameters were all set to 0. (D) Increased cell adhesion inhibits invasion. Adhesion parameters were set to −100, −50, and −25 for JLEP,LEP, JMEP,LEP, and JMEP,MEP, respectively. (E) Quantification of tissues with invasion at the end and the duct region of each tissue at 3000 MCS. Simulations were run 20 times each for the parameters described in C–D. (F) When tissue contractility is decreased by lowering the λv,MEP and λv,LEP to 2 and 1, respectively and lowering FPPP to 1 and 0.1 for homotypic and heterotypic cell interactions, cell invasion is inhibited. (G) Increased tissue contractility increases invasion from the duct regions. λv,MEP and λv,LEP were set to 50 and 25, respectively and FPP parameters were increased to 100 and 10 for homotypic and heterotypic cell interactions. (H) Quantification of tissues with invasion at the end and the duct region of each tissue at 3000 MCS. Simulations were run 20 times each for the parameters described in F–G.
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pcbi-1003997-g006: Patterns of cell invasion depend on cell adhesion and contractility.In the absence of proliferation, changing the adhesion parameter and the focal point plasticity parameter does not significantly alter tissue structure. (A) Images were generated using JLEP,LEP, JMEP,LEP, and JMEP,MEP values of −2, −1, −0.5; −10, −5, −2.5; −20, −10, −5; −40, −20, −10; and −100, −50, −25 with FPPP set to zero. (B) Images were generated using FPP parameters of 5 and 0.5, 25 and 2.5, 50 and 5, 75 and 7.5, and 100 and 10 for homotypic and heterotypic interactions, respectively. With high proliferation (mitosis every 65 MCS) and high apoptosis (1% probability), changing the adhesion parameter and the focal point plasticity parameter affects cell invasion. (C) When cell adhesion is decreased cells invade from the entire periphery of the tissue. Adhesion and FPP parameters were all set to 0. (D) Increased cell adhesion inhibits invasion. Adhesion parameters were set to −100, −50, and −25 for JLEP,LEP, JMEP,LEP, and JMEP,MEP, respectively. (E) Quantification of tissues with invasion at the end and the duct region of each tissue at 3000 MCS. Simulations were run 20 times each for the parameters described in C–D. (F) When tissue contractility is decreased by lowering the λv,MEP and λv,LEP to 2 and 1, respectively and lowering FPPP to 1 and 0.1 for homotypic and heterotypic cell interactions, cell invasion is inhibited. (G) Increased tissue contractility increases invasion from the duct regions. λv,MEP and λv,LEP were set to 50 and 25, respectively and FPP parameters were increased to 100 and 10 for homotypic and heterotypic cell interactions. (H) Quantification of tissues with invasion at the end and the duct region of each tissue at 3000 MCS. Simulations were run 20 times each for the parameters described in F–G.

Mentions: In our model, the ability of cells to adhere to each other is regulated by the cell adhesion and FPP parameters. In the absence of proliferation, changing these parameters did not significantly alter the structure of the tissue (Fig. 6A, B). However, as cells proliferated and produced an outward force, the roles of these parameters became more significant. When the value of the cell adhesion parameter was decreased, the cells no longer adhered to each other and invasion was observed around the entire periphery of the tissue (Fig. 6C, E). When the value of the cell adhesion parameter was increased, the strength of cell adhesion prevented invasion (Fig. 6D, E). Notably, high adhesion caused the morphology to remain micropapillary, whereas low adhesion led to the development of a cribriform morphology (Fig. 6D, E).


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)

Patterns of cell invasion depend on cell adhesion and contractility.In the absence of proliferation, changing the adhesion parameter and the focal point plasticity parameter does not significantly alter tissue structure. (A) Images were generated using JLEP,LEP, JMEP,LEP, and JMEP,MEP values of −2, −1, −0.5; −10, −5, −2.5; −20, −10, −5; −40, −20, −10; and −100, −50, −25 with FPPP set to zero. (B) Images were generated using FPP parameters of 5 and 0.5, 25 and 2.5, 50 and 5, 75 and 7.5, and 100 and 10 for homotypic and heterotypic interactions, respectively. With high proliferation (mitosis every 65 MCS) and high apoptosis (1% probability), changing the adhesion parameter and the focal point plasticity parameter affects cell invasion. (C) When cell adhesion is decreased cells invade from the entire periphery of the tissue. Adhesion and FPP parameters were all set to 0. (D) Increased cell adhesion inhibits invasion. Adhesion parameters were set to −100, −50, and −25 for JLEP,LEP, JMEP,LEP, and JMEP,MEP, respectively. (E) Quantification of tissues with invasion at the end and the duct region of each tissue at 3000 MCS. Simulations were run 20 times each for the parameters described in C–D. (F) When tissue contractility is decreased by lowering the λv,MEP and λv,LEP to 2 and 1, respectively and lowering FPPP to 1 and 0.1 for homotypic and heterotypic cell interactions, cell invasion is inhibited. (G) Increased tissue contractility increases invasion from the duct regions. λv,MEP and λv,LEP were set to 50 and 25, respectively and FPP parameters were increased to 100 and 10 for homotypic and heterotypic cell interactions. (H) Quantification of tissues with invasion at the end and the duct region of each tissue at 3000 MCS. Simulations were run 20 times each for the parameters described in F–G.
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Related In: Results  -  Collection

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

pcbi-1003997-g006: Patterns of cell invasion depend on cell adhesion and contractility.In the absence of proliferation, changing the adhesion parameter and the focal point plasticity parameter does not significantly alter tissue structure. (A) Images were generated using JLEP,LEP, JMEP,LEP, and JMEP,MEP values of −2, −1, −0.5; −10, −5, −2.5; −20, −10, −5; −40, −20, −10; and −100, −50, −25 with FPPP set to zero. (B) Images were generated using FPP parameters of 5 and 0.5, 25 and 2.5, 50 and 5, 75 and 7.5, and 100 and 10 for homotypic and heterotypic interactions, respectively. With high proliferation (mitosis every 65 MCS) and high apoptosis (1% probability), changing the adhesion parameter and the focal point plasticity parameter affects cell invasion. (C) When cell adhesion is decreased cells invade from the entire periphery of the tissue. Adhesion and FPP parameters were all set to 0. (D) Increased cell adhesion inhibits invasion. Adhesion parameters were set to −100, −50, and −25 for JLEP,LEP, JMEP,LEP, and JMEP,MEP, respectively. (E) Quantification of tissues with invasion at the end and the duct region of each tissue at 3000 MCS. Simulations were run 20 times each for the parameters described in C–D. (F) When tissue contractility is decreased by lowering the λv,MEP and λv,LEP to 2 and 1, respectively and lowering FPPP to 1 and 0.1 for homotypic and heterotypic cell interactions, cell invasion is inhibited. (G) Increased tissue contractility increases invasion from the duct regions. λv,MEP and λv,LEP were set to 50 and 25, respectively and FPP parameters were increased to 100 and 10 for homotypic and heterotypic cell interactions. (H) Quantification of tissues with invasion at the end and the duct region of each tissue at 3000 MCS. Simulations were run 20 times each for the parameters described in F–G.
Mentions: In our model, the ability of cells to adhere to each other is regulated by the cell adhesion and FPP parameters. In the absence of proliferation, changing these parameters did not significantly alter the structure of the tissue (Fig. 6A, B). However, as cells proliferated and produced an outward force, the roles of these parameters became more significant. When the value of the cell adhesion parameter was decreased, the cells no longer adhered to each other and invasion was observed around the entire periphery of the tissue (Fig. 6C, E). When the value of the cell adhesion parameter was increased, the strength of cell adhesion prevented invasion (Fig. 6D, E). Notably, high adhesion caused the morphology to remain micropapillary, whereas low adhesion led to the development of a cribriform morphology (Fig. 6D, E).

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