Potential Therapeutic Strategies for Lung and Breast Cancers through Understanding the Anti-Angiogenesis Resistance Mechanisms

Abstract

Breast and lung cancers are among the top cancer types in terms of incidence and mortality burden worldwide. One of the challenges in the treatment of breast and lung cancers is their resistance to administered drugs, as observed with angiogenesis inhibitors. Based on clinical and pre-clinical findings, these two types of cancers have gained the ability to resist angiogenesis inhibitors through several mechanisms that rely on cellular and extracellular factors. This resistance is mediated through angiogenesis-independent vascularization, and it is related to cancer cells and their microenvironment. The mechanisms that cancer cells utilize include metabolic symbiosis and invasion, and they also take advantage of neighboring cells like macrophages, endothelial cells, myeloid and adipose cells. Overcoming resistance is of great interest, and researchers are investigating possible strategies to enhance sensitivity towards angiogenesis inhibitors. These strategies involved targeting multiple players in angiogenesis, epigenetics, hypoxia, cellular metabolism and the immune system. This review aims to discuss the mechanisms of resistance to angiogenesis inhibitors and to highlight recently developed approaches to overcome this resistance.

Bevacizumab Plays a double-edged role in Neoadjuvant Therapy for Non-metastatic Breast Cancer: A Systemic Review and Meta-Analysis

“…It seems that Bev worked temporarily. As the conception of anti-angiogenic therapy is to induce tumor dormancy 55 , existing evidence of angiogenesis-independent vascularization, cancer cells metabolic reprogramming and tumor microenvironment indicates that tumor can tolerate with blocked angiogenesis 56 . With the withdrawal of Bev, cancer cells remaining in situ or hiding in the circulatory system might revive from dormancy 54 , leading to recurrence or metastasis.…”

Targeting Angiogenesis in Breast Cancer: Current Evidence and Future Perspectives of Novel Anti-Angiogenic Approaches

“…The activation of compensatory pro-angiogenic pathways in response to anti-VEGF therapy is a well-established mechanism of acquired resistance in tumors (Bergers and Hanahan, 2008;Ramadan et al, 2020). Blockade of the VEGF/VEGFR signaling pathway can aggravate hypoxia resulting in the upregulation of alternative angiogenic factors such as PDGFs, FGFs, chemokines, interleukin-8 (IL-8), Delta-like ligand-4, and ephrins (Bergers and Hanahan, 2008;Lord and Harris, 2010;Carmeliet and Jain, 2011).…”

“…Blockade of the VEGF/VEGFR signaling pathway can aggravate hypoxia resulting in the upregulation of alternative angiogenic factors such as PDGFs, FGFs, chemokines, interleukin-8 (IL-8), Delta-like ligand-4, and ephrins (Bergers and Hanahan, 2008;Lord and Harris, 2010;Carmeliet and Jain, 2011). Collectively, these angiogenic factors may rescue tumor vascularization despite the presence of the VEGF/VEGFR inhibitor (Bergers and Hanahan, 2008;Carmeliet and Jain, 2011;Ramadan et al, 2020).…”

“…However, upon the inhibition of angiogenic growth, vasculogenesis may become crucial to maintaining tumor vasculature (Brown, 2014). Hypoxiainduced by anti-VEGF therapy leads to the recruitment of pro-angiogenic bone marrow-derived cells (BMDCs) to the tumor microenvironment (Lord and Harris, 2010;Ramadan et al, 2020). BMDCs can restore vascularization of tumors thus enabling them to overcome hypoxia and become resistant to anti-VEGF drugs (Bergers and Hanahan, 2008;Lord and Harris, 2010).…”

Potential Regulatory Roles of GRK2 in Endothelial Cell Activity and Pathological Angiogenesis

“…Manipulation of tumor-associated angiogenesis represents a promising strategy to limit cancer progression; however, most of clinical tumor anti-angiogenesis drugs can easily cause drug resistance in patients (83)(84)(85). The main reason for drug resistance is that these drugs completely inhibit angiogenesis, which leads to an imbalance state that induces more severe angiogenesis.…”