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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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Invasion occurs preferentially at the ends of cylindrical ducts.(A) 0.5% probability of apoptosis, mitosis every 48 MCS, and random cell division: morphology begins as micropapillary and develops into cribriform with necrotic cells in the center and some invasion. Eventually the tissue becomes comedo. (B) 1% probability of apoptosis, mitosis every 32 MCS, and random cell division: morphology begins as micropapillary and develops into cribriform. As the tissue expands there are some necrotic cells in the duct and some cells break through the myoepithelial layer. (C) 0.5% probability of apoptosis, mitosis every 48 MCS, random cell division, and preferential proliferation: morphology begins as micropapillary and develops into cribriform morphology in the duct region with comedo morphology and invasion at the ends. Eventually the entire tissue becomes comedo. (D) 1% probability of apoptosis, mitosis every 32 MCS, random cell division, and preferential proliferation: morphology begins as micropapillary and develops into cribriform. As the tissue expands there are some necrotic cells in the duct and some cells break through the MEP layer. Quantification of tissues with invasion at the end and the duct region of each tissue at (E) 2000 MCS, (F) 2500 MCS and (G) 3000 MCS. Simulations were run 20 times each for the parameters described in A–D. Invasion occurs preferentially at the ends of the tissues.
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pcbi-1003997-g005: Invasion occurs preferentially at the ends of cylindrical ducts.(A) 0.5% probability of apoptosis, mitosis every 48 MCS, and random cell division: morphology begins as micropapillary and develops into cribriform with necrotic cells in the center and some invasion. Eventually the tissue becomes comedo. (B) 1% probability of apoptosis, mitosis every 32 MCS, and random cell division: morphology begins as micropapillary and develops into cribriform. As the tissue expands there are some necrotic cells in the duct and some cells break through the myoepithelial layer. (C) 0.5% probability of apoptosis, mitosis every 48 MCS, random cell division, and preferential proliferation: morphology begins as micropapillary and develops into cribriform morphology in the duct region with comedo morphology and invasion at the ends. Eventually the entire tissue becomes comedo. (D) 1% probability of apoptosis, mitosis every 32 MCS, random cell division, and preferential proliferation: morphology begins as micropapillary and develops into cribriform. As the tissue expands there are some necrotic cells in the duct and some cells break through the MEP layer. Quantification of tissues with invasion at the end and the duct region of each tissue at (E) 2000 MCS, (F) 2500 MCS and (G) 3000 MCS. Simulations were run 20 times each for the parameters described in A–D. Invasion occurs preferentially at the ends of the tissues.

Mentions: Experiments in culture have revealed that asymmetries in tissue geometry lead to regional differences in endogenous mechanical stress, which result from the concentration of mechanical stresses by otherwise isotropically contracting cells in the tissue [29], [30]. Furthermore, tumor cells have been observed to proliferate and invade preferentially from regions of high mechanical stress both in culture and in vivo[25]. We next explored whether tissue geometry affected the morphology that emerged by modeling a cross-section through a cylindrical (ductal) tissue. Throughout the tissue, the morphology of DCIS that emerged appeared to be fairly consistent; however, we observed that cells invaded more frequently from the ends than from the center of the duct (Fig. 5A, B, E–G). Previously, we found experimentally that tumor cells proliferate almost twice as frequently when they are located at the ends of ducts engineered in culture [25]. When we included this pattern of proliferation in our model, we observed an increase in the number of tissues in which cells invaded from the ends (Fig. 5C, D, E–G). We also noticed some differences in morphology. For example, in the simulations shown in Fig. 5C, the duct region of the tissue develops into a cribriform morphology while the end region becomes comedo with invasion. Experimentally, preferential invasion has been attributed to elevated levels of mechanical stress [25], possibly due to mechanical regulation of YAP/TAZ [61]. When cells push and pull on each other within a tissue, varying levels of endogenous mechanical stress will emerge across the tissue due to asymmetries in the tissue geometry [29], [31]. Therefore, we next explored the effect of altering tissue contractility in this 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)

Invasion occurs preferentially at the ends of cylindrical ducts.(A) 0.5% probability of apoptosis, mitosis every 48 MCS, and random cell division: morphology begins as micropapillary and develops into cribriform with necrotic cells in the center and some invasion. Eventually the tissue becomes comedo. (B) 1% probability of apoptosis, mitosis every 32 MCS, and random cell division: morphology begins as micropapillary and develops into cribriform. As the tissue expands there are some necrotic cells in the duct and some cells break through the myoepithelial layer. (C) 0.5% probability of apoptosis, mitosis every 48 MCS, random cell division, and preferential proliferation: morphology begins as micropapillary and develops into cribriform morphology in the duct region with comedo morphology and invasion at the ends. Eventually the entire tissue becomes comedo. (D) 1% probability of apoptosis, mitosis every 32 MCS, random cell division, and preferential proliferation: morphology begins as micropapillary and develops into cribriform. As the tissue expands there are some necrotic cells in the duct and some cells break through the MEP layer. Quantification of tissues with invasion at the end and the duct region of each tissue at (E) 2000 MCS, (F) 2500 MCS and (G) 3000 MCS. Simulations were run 20 times each for the parameters described in A–D. Invasion occurs preferentially at the ends of the tissues.
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pcbi-1003997-g005: Invasion occurs preferentially at the ends of cylindrical ducts.(A) 0.5% probability of apoptosis, mitosis every 48 MCS, and random cell division: morphology begins as micropapillary and develops into cribriform with necrotic cells in the center and some invasion. Eventually the tissue becomes comedo. (B) 1% probability of apoptosis, mitosis every 32 MCS, and random cell division: morphology begins as micropapillary and develops into cribriform. As the tissue expands there are some necrotic cells in the duct and some cells break through the myoepithelial layer. (C) 0.5% probability of apoptosis, mitosis every 48 MCS, random cell division, and preferential proliferation: morphology begins as micropapillary and develops into cribriform morphology in the duct region with comedo morphology and invasion at the ends. Eventually the entire tissue becomes comedo. (D) 1% probability of apoptosis, mitosis every 32 MCS, random cell division, and preferential proliferation: morphology begins as micropapillary and develops into cribriform. As the tissue expands there are some necrotic cells in the duct and some cells break through the MEP layer. Quantification of tissues with invasion at the end and the duct region of each tissue at (E) 2000 MCS, (F) 2500 MCS and (G) 3000 MCS. Simulations were run 20 times each for the parameters described in A–D. Invasion occurs preferentially at the ends of the tissues.
Mentions: Experiments in culture have revealed that asymmetries in tissue geometry lead to regional differences in endogenous mechanical stress, which result from the concentration of mechanical stresses by otherwise isotropically contracting cells in the tissue [29], [30]. Furthermore, tumor cells have been observed to proliferate and invade preferentially from regions of high mechanical stress both in culture and in vivo[25]. We next explored whether tissue geometry affected the morphology that emerged by modeling a cross-section through a cylindrical (ductal) tissue. Throughout the tissue, the morphology of DCIS that emerged appeared to be fairly consistent; however, we observed that cells invaded more frequently from the ends than from the center of the duct (Fig. 5A, B, E–G). Previously, we found experimentally that tumor cells proliferate almost twice as frequently when they are located at the ends of ducts engineered in culture [25]. When we included this pattern of proliferation in our model, we observed an increase in the number of tissues in which cells invaded from the ends (Fig. 5C, D, E–G). We also noticed some differences in morphology. For example, in the simulations shown in Fig. 5C, the duct region of the tissue develops into a cribriform morphology while the end region becomes comedo with invasion. Experimentally, preferential invasion has been attributed to elevated levels of mechanical stress [25], possibly due to mechanical regulation of YAP/TAZ [61]. When cells push and pull on each other within a tissue, varying levels of endogenous mechanical stress will emerge across the tissue due to asymmetries in the tissue geometry [29], [31]. Therefore, we next explored the effect of altering tissue contractility in this 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