Breaking through to the Other Side: Microenvironment Contributions to DCIS Initiation and Progression

Abstract

Refinements in early detection, surgical and radiation therapy, and hormone receptor-targeted treatments have improved the survival rates for breast cancer patients. However, the ability to reliably identify which non-invasive lesions and localized tumors have the ability to progress and/or metastasize remains a major unmet need in the field. The current diagnostic and therapeutic strategies focus on intrinsic alterations within carcinoma cells that are closely associated with proliferation. However, substantial accumulating evidence has indicated that permissive changes in the stromal tissues surrounding the carcinoma play an integral role in breast cancer tumor initiation and progression. Numerous studies have suggested that the stromal environment surrounding ductal carcinoma in situ (DCIS) lesions actively contributes to enhancing tumor cell invasion and immune escape. This review will describe the current state of knowledge regarding the mechanisms through which the microenvironment interacts with DCIS lesions focusing on recent studies that describe the contributions of myoepithelial cells, fibroblasts and immune cells to invasion and subsequent progression. These mechanisms will be considered in the context of developing biomarkers for identifying lesions that will progress to invasive carcinoma and/or developing approaches for therapeutic intervention.

Keywords: DCIS; Ductal carcinoma in situ; Fibroblast; Immune; Mammary gland; Myoepithelial; Tumor microenvironment.

Figure 1:. Morphologic variation of human DCIS and the tumor-associated stroma.

A) Example of low grade, solid type DCIS. Black arrows point to examples of the retained basement membrane and myoepithelial cells of the involved ducts. The stroma has minimal (*) to moderate (+) amounts of pinkstaining, acellular collagen. The overall stromal cellularity is low (scale bar=200 uM). B) Low grade, cribriform type DCIS with marked accumulation of dark pink-staining collagen throughout the stroma. The black arrow points to an example of fibroblasts demonstrating slightly elongated (spindle) nuclei. (scale bar=200 uM). C) High grade, cribriform type DCIS; accumulation of apoptotic debris is beginning within lumen (black arrow). The stroma (*) has a moderate accumulation of collagen throughout, with moderate stromal cellularity. A small focus of lymphocytes is outlined at the top of the image (scale bar=200 uM). D) High grade, solid type DCIS; there is a heavy, extensive lymphocytic infiltrate (outlined in black) (scale bar=200 uM). E,F) Low power image of a high-grade, comedo type DCIS with microinvasion (scale bar=500 uM). The boxed area is shown in panel F at high power; DCIS with comedo necrosis (*) is outlined in red, while the black arrows point to foci of microinvasive carcinoma. There is a marked lymphocyte infiltrate throughout the stroma (scale bar=200 uM).

Figure 2:. Summary of microenvironment contributions to DCIS progression.

Multiple cell types, including myoepithelial cells, fibroblasts, myeloid cells and lymphocytes have been examined in the context of DCIS progression. Specific molecules that contribute to both tumor suppression and promotion are listed as detailed in the respective sections within this review.

Figure 3:. Macrophage infiltration in premalignant lesions.

F4/80 staining shows that macrophages are recruited to pre-invasive lesions in (A) p53^−/− PN1a, (B) p53^−/− PN1b, and (C) C3(1)TAg mouse models. D) CD68 staining shows immune cell infiltration in human DCIS.