Wound Healing Fluid Reflects the Inflammatory Nature and Aggressiveness of Breast Tumors

Abstract

Wound healing fluid that originates from breast surgery increases the aggressiveness of cancer cells that remain after the surgery. We determined the effects of the extent of surgery and tumor-driven remodeling of the surrounding microenvironment on the ability of wound-healing to promote breast cancer progression. In our analysis of a panel of 34 cytokines, chemokines, and growth factors in wound healing fluid, obtained from 27 breast carcinoma patients after surgery, the levels of several small molecules were associated with the extent of cellular damage that was induced by surgery. In addition, the composition of the resulting wound healing fluid was associated with molecular features of the removed tumor. Specifically, IP-10, IL-6, G-CSF, osteopontin, MIP-1a, MIP-1b, and MCP1-MCAF were higher in more aggressive tumors. Altogether, our findings indicate that the release of factors that are induced by removal of the primary tumor and subsequent wound healing is influenced by the extent of damage due to surgery and the reactive stroma that is derived from the continuously evolving network of interactions between neoplastic cells and the microenvironment, based on the molecular characteristics of breast carcinoma cells.

The Composition of Surgical Wound Fluids from Breast Cancer Patients is Affected by Intraoperative Radiotherapy Treatment and Depends on the Molecular Subtype of Breast Cancer

“…Similar experiments were also conducted by Agresti et al who confirmed that the composition of SWF depends not only on the type of surgical procedure (quadrantectomy, mastectomy), but also on the aggressiveness of the tumor (in situ vs invasive), molecular subtype (luminal vs. triple-negative), the size of the tumor, staging (G2 or G3), and lymph node status (positive or negative for cancer cells). They suggested that the composition of surgical wound fluids collected from the tumor bed of breast cancer patients reflects the inflammatory nature and aggressiveness of the breast tumor [8]. The authors analyzed a panel of 34 cytokines, chemokines, and growth factors in the SWF of breast cancer patients and found, that the concentrations of IP-10, IL-6, G-CSF, osteoponin, MIP-1 alpha, MIP-1 beta, and MCP1-MCAF were higher in more aggressive tumors.…”

“…It is one of the major cytokines present in SWF after surgery, especially in patients after neoadjuvant chemotherapy [9]. Agresti et al also found a higher concentration of this cytokine in patients after radical mastectomy than in those after quadrantectomy [8].…”

“…Regulates T cell recruitment under homeostatic and inflammatory conditions [5] G-CSF Controls the maturation of neutrophils [8] HGF Induces cancer cell migration and invasion, wound healing, angiogenesis [21] IL-1 beta Inhibits the proliferation of some cancers, amplifies the function of dendritic cells, stimulates the proliferation and differentiation of CD4, CD8 and natural killer (NK) cells, increases antibody production by lymphocytes B, and finally increases the expression of adhesion molecules on vascular endothelium [22] IL-12 Induction of Th1 cells [23,24] IL-13 Induces the activation of M2 macrophages, polarizes M2a macrophages and induces migration and invasion of breast cancer cells [25,26] [27,28] IL-8 Increased the formation of primary and secondary tumor spheres, as well as the cancer stem cell phenotype in BC [29] MCP-1 Increases monocyte mobilization and poor survival and is involved in monocyte polarization to M2-cells [30] MCP-3 Attracts monocytes, dendritic cells (DCs), and activated T lymphocytes, to invasion sites [31] MIF Induces myeloid-derived suppressor cells in tumor microenvironment [32] PDGF-beta Regulates metastasis and vascular remodeling in cancer [33]…”

“…Although SWF is rich in biological factors, the expression of these factors and how they interact with tumor cells, has not been entirely explained. Agresti et al and Wang et al analyzed the composition of SWF from breast cancer patients in detail [8,9]. They found that the composition of SWF differs between patients depending on the treatment (quadrantectomy or mastectomy), type (invasive or in situ) and the molecular subtype of breast cancer (BC) (luminal or triple-negative).…”

Surgical Wound Fluids from Patients with Breast Cancer Reveal Similarities in the Biological Response Induced by Intraoperative Radiation Therapy and the Radiation-Induced Bystander Effect—Transcriptomic Approach

“…Surgical excision of the primary tumor induces a wound healing response and inflammatory processes that alter the local environment and stimulate the growth kinetics of the remaining cancer foci, thereby potentially promoting metastasis [7][8][9]. Studies using global transcriptome analysis of a panel of triple-negative breast cancer (TNBC) cell lines have found that stimulation with surgical wound fluid (SWF) significantly increases the expression of genes related to wound response, cytokine activity, and locomotory characteristics [10].…”