Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment

Abstract

The interactions of transformed cells with the surrounding stromal cells are of importance for tumor progression and metastasis. The relevance of adipocyte-derived factors to breast cancer cell survival and growth is well established. However, it remains unknown which specific adipocyte-derived factors are most critical in this process. Collagen VI is abundantly expressed in adipocytes. Collagen -/-mice in the background of the mouse mammary tumor virus/polyoma virus middle T oncogene (MMTV-PyMT) mammary cancer model demonstrate dramatically reduced rates of early hyperplasia and primary tumor growth. Collagen VI promotes its growthstimulatory and pro-survival effects in part by signaling through the NG2/chondroitin sulfate proteoglycan receptor expressed on the surface of malignant ductal epithelial cells to sequentially activate Akt and β-catenin and stabilize cyclin D1. Levels of the carboxyterminal domain of collagen VIα3, a proteolytic product of the fulllength molecule, are dramatically upregulated in murine and human breast cancer lesions. The same fragment exerts potent growth-stimulatory effects on MCF-7 cells in vitro. Therefore, adipocytes play a vital role in defining the ECM environment for normal and tumor-derived ductal epithelial cells and contribute significantly to tumor growth at early stages through secretion and processing of collagen VI.

Does Breast Size Modify the Association between Mammographic Density and Breast Cancer Risk?

“…The fat tissue secretes and/or produces a number of biologically active substances (14), commonly named adipo(cyto)kines (15). Several studies have suggested that adipocyte secreted proteins could stimulate proliferation in malignant cells (16)(17)(18). Further, estrogens synthesized from androgens by the aromatase enzyme in peripheral adipose tissues ; continuous), age at mammography (5-y interval), breast cancer family history (none, first degree, second degree), age at menarche (V13 y, >13 y), number of full-term pregnancies (0, 1-2, z3), age at first full-term pregnancy (<30 y, z30 y), menopausal status and use of hormone replacement therapy (premenopausal, postmenopausal and: current estrogen therapy, current estrogen plus progestin therapy, ex-estrogen therapy, ex-estrogen plus progestin therapy, never hormone therapy), and race.…”

Adipose Tissue

“…Of particular interest are the specific interactions of transformed ductal epithelial cells with the mammary fat pad, relevant for the developmental aspects as well as for the wellestablished dependence of mammary tumors on adipose tissue during early stages of lesion growth. Our recent work on collagen VI has underlined the importance of this extracellular matrix component, which is highly enriched in adipose tissue for the growth of such mammary ductal epithelial tumors (18).…”

“…These adipocytes can release protein and lipid derivatives that are highly proangiogenic and have an impact on the preexisting vasculature. Finally, the unique extracellular matrix environment of adipose tissue hosts a number of additional cells such as macrophages and offers unique growth potential for transformed cells such as breast cancer cells (18,19).…”

The extracellular matrix in breast cancer predicts prognosis through composition, splicing, and crosslinking

“…Laminin-111/Ln-1 has three head domains which can crosslink into a soft cohesive 3D network, whereas other laminin isoforms with truncated head domains, such as laminin-332/Ln-5, laminin-511/Ln-10 or laminin-521/Ln-11, cannot form a network [22,29], and do not support normal epithelial cell function in vitro, despite the fact that all these isoforms present similar tail domains to cells [16]. Furthermore, some evidence suggests that laminin-332, or collagen IV may support tumor invasion or aggressiveness [30][31][32].…”