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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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DCIS morphologies.Shown are histology sections (left) and schematic representations (right). (A) Micropapillary tumors contain additional epithelial cells within the lumen. (B) Cribriform tumors are characterized by ducts filled with cells that form multiple lumena. (C) Solid tumors have completely filled ducts. (D) Comedo tumors are solid with a necrotic core resulting from nutrient insufficiency [6], [9], [10]. Basement membrane is shown in black, myoepithelial (MEP) cells in blue, luminal epithelial (LEP) cells in green, and necrotic cells in red. Scale bars, 100 µm.
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pcbi-1003997-g001: DCIS morphologies.Shown are histology sections (left) and schematic representations (right). (A) Micropapillary tumors contain additional epithelial cells within the lumen. (B) Cribriform tumors are characterized by ducts filled with cells that form multiple lumena. (C) Solid tumors have completely filled ducts. (D) Comedo tumors are solid with a necrotic core resulting from nutrient insufficiency [6], [9], [10]. Basement membrane is shown in black, myoepithelial (MEP) cells in blue, luminal epithelial (LEP) cells in green, and necrotic cells in red. Scale bars, 100 µm.

Mentions: The mammary gland is a highly organized, branched ductal network of luminal epithelial cells surrounded by myoepithelium and basement membrane embedded in stroma [1], [2]. Reciprocal signaling between the cells and their surrounding microenvironment maintains the organization and function of the mammary epithelium. Disruption of these cues and the resulting architecture leads to ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) [1]–[3]. DCIS is defined as increased proliferation of ductal epithelial cells in the absence of basement membrane degradation [4]–[6]. Whereas DCIS is not life-threatening, some of these lesions may progress to IDC if left untreated [7], [8]. Pathologists classify DCIS by four morphologies: micropapillary, cribriform, solid, and comedo. Micropapillary tumors contain additional epithelial cells within the lumen of the duct (Fig. 1A). Cribriform tumors are characterized by ducts filled with cells that form multiple lumena (Fig. 1B). Solid tumors have completely filled ducts (Fig. 1C). Comedo tumors are solid with a necrotic core resulting from nutrient insufficiency (Fig. 1D) [6], . Of these four morphologies, comedo lesions have the greatest risk for recurrence after breast-conserving surgery [11]. Due to the increased use of mammographic screening, the number of observed incidences of DCIS has increased dramatically, by 500% and 290% between 1983 and 2003 for women over 50 and under 50, respectively [12]. DCIS currently accounts for ∼20% of all breast cancers diagnosed in the U.S. [8].


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)

DCIS morphologies.Shown are histology sections (left) and schematic representations (right). (A) Micropapillary tumors contain additional epithelial cells within the lumen. (B) Cribriform tumors are characterized by ducts filled with cells that form multiple lumena. (C) Solid tumors have completely filled ducts. (D) Comedo tumors are solid with a necrotic core resulting from nutrient insufficiency [6], [9], [10]. Basement membrane is shown in black, myoepithelial (MEP) cells in blue, luminal epithelial (LEP) cells in green, and necrotic cells in red. Scale bars, 100 µm.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003997-g001: DCIS morphologies.Shown are histology sections (left) and schematic representations (right). (A) Micropapillary tumors contain additional epithelial cells within the lumen. (B) Cribriform tumors are characterized by ducts filled with cells that form multiple lumena. (C) Solid tumors have completely filled ducts. (D) Comedo tumors are solid with a necrotic core resulting from nutrient insufficiency [6], [9], [10]. Basement membrane is shown in black, myoepithelial (MEP) cells in blue, luminal epithelial (LEP) cells in green, and necrotic cells in red. Scale bars, 100 µm.
Mentions: The mammary gland is a highly organized, branched ductal network of luminal epithelial cells surrounded by myoepithelium and basement membrane embedded in stroma [1], [2]. Reciprocal signaling between the cells and their surrounding microenvironment maintains the organization and function of the mammary epithelium. Disruption of these cues and the resulting architecture leads to ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) [1]–[3]. DCIS is defined as increased proliferation of ductal epithelial cells in the absence of basement membrane degradation [4]–[6]. Whereas DCIS is not life-threatening, some of these lesions may progress to IDC if left untreated [7], [8]. Pathologists classify DCIS by four morphologies: micropapillary, cribriform, solid, and comedo. Micropapillary tumors contain additional epithelial cells within the lumen of the duct (Fig. 1A). Cribriform tumors are characterized by ducts filled with cells that form multiple lumena (Fig. 1B). Solid tumors have completely filled ducts (Fig. 1C). Comedo tumors are solid with a necrotic core resulting from nutrient insufficiency (Fig. 1D) [6], . Of these four morphologies, comedo lesions have the greatest risk for recurrence after breast-conserving surgery [11]. Due to the increased use of mammographic screening, the number of observed incidences of DCIS has increased dramatically, by 500% and 290% between 1983 and 2003 for women over 50 and under 50, respectively [12]. DCIS currently accounts for ∼20% of all breast cancers diagnosed in the U.S. [8].

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