Oncogenic Linear Collagen VI of Invasive Breast Cancer Is Induced by CCL5

Abstract

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.

Tumor-associated collagen signatures: pushing tumor boundaries

“…The same study used a parallel in vitro collagen deposition study and mass spectrometry to make an educated guess at which the isoform of collagen is highest in the TACS3 signatures. The proteome analysis of in vitro collagen showed collagen VI, which was seen using immunohistochemistry to be highly present in TACS3 of human tumor biopsy samples [7]. This represents the first reported biochemical target of TACS3.…”

“…Many research papers which examine TACS are corollary in nature, with a large focus on describing the presence and prognostic value of TACS3. Our group recently published the linear formation of collagen in vitro by a breast cancer cell co-culture, which marks the first TACS publication to have a laboratory intervention experiment pertaining to linearized ECM of breast cancer [7]. TACS is largely described in breast tumors; however, orderly collagen formation is also seen in malignant ovarian tumors, with one study showing "increased normality" of collagen deposition [8].…”

“…TACS is detectable using strategic histological sections made transversely at the tumor border. Recently, TACS3 at the tumor border of invasive breast tumors have been easily identified using classic hematoxylin and eosin staining [7]. However, this stain is only specific for collagen, not collagen isoforms.…”

“…When CCL5 is blocked, linear collagen deposition is prohibited and a randomly arranged layer of ECM is produced. Moreover, when MDA-MB-231 cells are reseeded on the linear matrix, they show high levels of proliferation and formation into road-like structures, the type of organized invasive behavior seen in enhanced metastatic abilities [7]. Velez et al mirror these findings, but with "collagen-induced network phenotypes" using MDA-MB-231 cells in collagen gels.…”

The CCL5/CCR5 Axis in Cancer Progression

“…In Table 2, we summarize the effects of disrupting the CCL5/CCR5 axis in solid tumors. [117] Inhibited angiogenesis, reduced metastasis and improved survival in mouse models [118] Reduced immune-suppressive myeloid cells, increased antitumor immunity and reduced tumor growth in mouse models (in presence of CCL5-targeting siRNA) [78] Reduced mice tumor growth and thoracic metastasis (in presence of anti-IL-6R) [119] Reduced metastasis in mouse models Enhanced cell killing by doxorubicin in vitro [43] Reduced resistance to trastuzumab due to CCL5 overexpression [120] Anti-CCL5 antibodies Counteracted the ability of MSCs to induce metastasis in tumor xenografts [10] Inhibited collagen VI production by fibroblasts in response to the paracrine coculture of adipose-derived stem cells and tumor cells [121] Breast phyllodes Maraviroc Inhibited monocyte recruitment and tumor growth in patient-derived mouse xenografts [122] Cholangio-carcinoma Anti-CCL5 antibody, maraviroc Decreased cell invasion and CCR5 expression induced by MSCs [123] Colon cancer…”