Department of Biochemistry and Bioinformatics, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh, India
Received: September 26, 2018; Accepted: November 27, 2018; Published: November 30, 2018
Citation: Kumari S (2018) Targeting Tumor Microenvironment and Metabolic Aberration Against TNBC. Insights Biomed Vol.3 No.3:14. doi:10.21767/2572-5610.100049.
Triple Negative Breast Cancer (TNBC) is a highly heterogeneous and aggressive subtype of breast cancer. Tumor microenvironment has been identified as a major regulator of carcinogenesis and imparting drug resistance to the proliferating cancer cells. Microenvironment conditions has been identified to promote altered metabolism which is one of the major factors in contributing to drug resistance of TNBC. Thus, identification of specific metabolic inhibitor and use of combinational drug therapy may be proven as a mainstay of treatment for triple negative breast cancer. Oxidative stress caused by ROS a byproduct of metabolic processes is associated with tumorigenesis and metastasis of breast cancer. Generally high levels of ROS have been identified in TME which contributes in cancer progression and aggressiveness. Thus, early detection of ROS level may be clinically advantageous to prevent further progression and aggressiveness of TNBC.
TNBC; Tumor microenvironment; Oncometabolites
Triple negative breast cancer and tumor microenvironment
Triple Negative Breast Cancer (TNBC) is a highly heterogeneous, aggressive and fatal subtype of breast cancer which is negative for estrogen receptors (ER-), progesterone receptors (PR-) and human epidermal growth factor receptor 2 (HER2-). The present communication highlights on the importance of drug synergism which implies targeted drug therapy as different molecular regulators . Special emphasis has been given to oncometabolites and ROS as they are important part of tumor microenvironment which undergoes which greatly influence and promote cancer metastasis. Tumor microenvironment (TME) has been identified as a major regulator of carcinogenesis, thus exploring this complex mechanism may bring an insight on understanding tumorigenesis. Exploring TME and its specific biomarkers related to metabolic aberration can be used to predict the clinical outcome may be proven as a promising approach in treatment of TNBCs . In addition to neoplastic cells, the breast microenvironment is rich in extracellular matrix (ECM), stromal cell, endothelial cells, immune cells, fibroblasts, and adipocytes. TMC requires soluble factors like PDGF, TGF-β, EGF for communication and interactions which increases the aggressiveness of the disease. Cancer-associated fibroblasts (CAFs) are predominated in cancer stroma and affect the tumor microenvironment such that they promote cancer initiation, angiogenesis, epithelial-mesenchymal transition (EMT) invasion and metastasis. In breast cancer, CAFs not only promote tumor progression, but also induce therapeutic drug resistances and best example can be given as paclitaxel. Collagen type I secreted by CAFs contributes to decreasing chemotherapeutic drug uptake in tumors and plays a significant role in regulating tumor sensitivity to a variety of chemotherapies . Chemotherapy and radiation therapy induce DNA damage in fibroblasts which ultimately, promote secretion of WNT16B and consequently result in aggressiveness of the disease and induce mitoxantrone (MIT) resistance by NF-κβ pathway activation .
Stemness in tumor microenvironment of TNBC
TNBC stem cells exhibit unique abilities including self-renewal, differentiation potential, and drug resistance to chemo- and/ or radiotherapy, which contributes to the development of aggressiveness and metastatic lesions . Indeed, exposure various treatments promote “stemness” in non-stem cancer cells, which explain failure of clinical improvement. Acquisition of stemness involves epithelial-mesenchymal transition (EMT), in which epithelial cells are transformed into a mesenchymal phenotype characterized by increased capacities for migration, invasiveness, and resistance to apoptosis. Many approaches have been made to overcome the resistance against conventional therapies which include targeted therapy, immunotherapies and targeting natural killer cells employed to induce a T cell response .
Oncometabolite in tumor microenvironment
Altered metabolic pathways promote cancer proliferation, adapt to nutrient limited conditions, and develop drug resistance phenotypes. The metabolic pathways are network of interacting genes, proteins and metabolite reactions. These properties are regulated at several checkpoints in normal cells. Altered metabolism is considered as one of the hallmarks of cancer cells and linked to cancer drug resistance. Drug resistance is linked to specific metabolic aberrations of TNBC, notably an increased use of glucose and the amino acid glutamine fueling anabolic processes. Altered metabolism contributes also to modulation of apoptosis, angiogenesis and drug targets, conferring a resistant phenotype. As a modality to overcome drug resistance, a variety of experimental compounds inhibiting key metabolic pathways emerged as a promising approach to potentiate the standard treatments for TNBC in preclinical studies. Metabolic rewiring is central to the pathogenesis of TNBC and is a critical component of the tumorigenic program driven by K-RAS, the signature mutation in this malignancy. The metabolic changes in cancer cells, such as the Warburg effect, allow available resources to be converted into biomass in an efficient manner. Aberrant (glycolytic) metabolism allows cancer cells to resist standard treatment through modulation of apoptosis and angio-genesis, as well as affecting drug transport and targets. Microenvironment conditions promote the Warburg effect in metabolism . Metabolic inhibitor in combination with chemotherapy remains the mainstay of treatment for triple negative breast cancer (TNBC) despite the promise of new targeted and biologic agents. The role of specific chemotherapy agents in the treatment of TNBC thus identification of molecular biomarkers to predict response to specific chemotherapy is required to further improve treatment strategies with the current chemotherapy and future combinations with targeted therapies finds a novel approach in treatment of TNBC.
Oxidative stress and TME
It is well established fact that there is a close association between breast cancer and TME. Among various factors regulating cancer progression and metastasis, oxidative stress finds an important role in carcinogenesis [8,9]. Oxidative stress has been identified to causes metabolic imbalance also to affect the levels of ROS and antioxidants. Accumulation of ROS in TME induce impact on cell signaling through electron transport chain in mitochondria or activation of the NADPH oxidases (NOX4) by paracrine mode. Overexpression of NOX4 can result in tumorigenesis. ROS also helps in the differentiation of normal fibroblasts into myofibroblasts, which enhances ROS levels in the microenvironment [10-12]. Myofibroblasts secrets high levels of type I collagen which contributes to mammary tumor formation, metastasis and drug resistance by decreasing the uptake of the chemotherapeutic drug. Serine proteases like metalloproteinases (MMP) such as MMP-2, MMP-3, and MMP-9 which has important role in cancer metastasis has been reported to play an important role in increasing ROS levels. Growth factors such as TGF-β, IGF, TNF-α, or PDGF stimulate ROS production through NOX [13-16]. Once activated, the tumor microenvironment network produces large amounts of ROS, initiating tumor growth. Thus, detection of high levels of ROS in TME early diagnosis would be clinically advantageous to prevent further progression and aggressiveness of TNBC (Figure 1).
Metabolic alteration is important for tumor development and progression and is a hallmark of cancer. Tumor microenvironment (TME) has an important interaction between neoplastic cells and ECM as they recruit to form the tumor-associated stroma and has an initiative in tumor initiation, progression, metastasis and drug resistance. Aberrant metabolism allows cancer cells to resist standard treatment through modulation of apoptosis and angio-genesis, as well as affecting drug transport and targets. Microenvironment conditions associated with stemness, signal transduction, ROS and metabolic aberration enhance the adverse effect and promote the survival and aggressiveness of tumor. Thus, therapeutic strategies have to be identified as a specific biomarker associated with TME and metabolic change.
Identification and development of specific targeted therapy against tumor microenvironment especially targeting stem cells and oncometabolite by the application of combinational drug therapy method finds a promising approach in targeting tumor microenvironment in treatment of TNBC.