In 2006, a new model of invasive breast tumor emerged and, since 2011, is gaining recognition and research momentum. "Tumor-associated collagen signatures" describe 3 distinct layers of collagen which radiate outward in shells from the main body of the tumor. The outermost layer (TACS3) features branches of collagen radiating away from the tumor, 90°perpendicular to the tumor surface. TACS3 increases tumor span and correlates directly with metastasis, though presently difficult to detect in breast tissue. TACS is an emerging model but has been validated by multiple labs in vitro and in vivo, specifically for breast cancer prognostics. Newly recognized and accepted tumor borders will impact both R0 resections and downstream surgical reconstruction. This review aims to comprehensively introduce and connect the ranging literature on linearized collagen of invasive tumor borders. Using PubMed keyword searches containing "aligned," "linear," "oriented," and "organized," we have gathered the studies on TACS, integrated the concept into the clinic, and projected future platforms.
The triple-negative breast tumor boundary is made of aligned, linear collagen. The pro-oncogenic impact of linear collagen is well established; however, its mechanism of formation is unknown. An in vitro analogue of the tumor border is created by a co-culture of MDA-MB-231 cells, adipose derived stem cells, and dermal fibroblasts. Decellularization of this co-culture after seven days reveals an extracellular matrix that is linear in fashion, high in pro-oncogenic collagen type VI, and able to promote invasion of reseeded cells. Further investigation revealed linear collagen VI is produced by fibroblasts in response to a paracrine co-culture of adipose derived stem cells and MDA-MB-231, which together secrete high levels of the chemokine CCL5. The addition of monoclonal antibody against CCL5 to the co-culture results in an unorganized matrix with dramatically decreased collagen VI. Importantly, reseeded cells do not exhibit pro-oncogenic behavior. These data illustrate a cellular mechanism, which creates linear extracellular matrix (ECM) in vitro, and highlight a potential role of CCL5 for building striated tumor collagen in vivo.
Breast reconstruction proceeding cancer treatment carries risk, regardless of the type of surgery. From fat grafting, to flap placement, to implants, there is no guarantee that reconstruction will not stimulate breast cancer recurrence. Research in this field is clearly divided into two parts: scientific interventional studies and clinical retrospective evidence. The reconstructive procedure offers hypoxia, a wound microenvironment, bacterial load, adipose derived stem cells; agents shown experimentally to cause increased cancer cell activity. This is compelling scientific evidence which serves to bring uncertainty and fear to the reconstructive procedure. In the absence of clinical evidence, this laboratory literature landscape is now informing surgical choices. Curiously, clinical studies have not shown a clear link between breast cancer recurrence and reconstructive surgery. Where does that leave us? This review aims to analyze the science and the surgery, thereby understanding the oncological fear which accompanies breast cancer reconstruction.
Introduction: In the surgical world of breast cancer reconstruction, fat grafting is commonly viewed as an oncogenic risk. Scientific studies add confusion, given the stark lack of clinical evidence suggesting pro-oncogenic links. Typically, classic migration assays (e.g., Boyden chamber) between adipose-derived stem cells and breast cancer cells define this cell relationship as pro-oncogenic. Objective: We sought to develop a new migration model which better explains existing clinical data. Methods: Silicon chambers were used to seed isolated populations of cells simultaneously in culture dish. Once cells had adhered, chambers were removed and cells were allowed to follow natural trophic cues. Multiple permutations of MDA-MB-231, MCF-7, HS-27, and ASCs were engineered. Cells were stained with MitoTracker for fluorescent visualization. A human cytokine array (RayBiotech) was performed on the media of migrating assays. Cellular tropism and blot intensity were quantitatively measured in Image J. Results: An in vitromodel was successfully constructed where ASCs reproducibly and freely migrated. Cytokine arrays reveal higher levels of IL-6 and CCL2 in the media of Boyden chambers containing ASCs and MDA-MB-231, compared to the novel assay, comprised of the same cell numbers, types, and incubation times. Conclusion: These data collectively show for the first time the attraction of ASCs to malignant breast cancer cells; a phenomenon which many ASC studies infer. The cytokine profile of the novel system described is less oncogenic than the commonly described Boyden chamber. These data integrate better into the clinical data, which fail to link cancer recurrence with fat grafting.
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