Tipping Tumor Microenvironment against Drug Resistance

Abstract

Tumor microenvironment (TME) represents a structural hallmark of solid neoplasms, and plays a critical role in multiple aspects of oncologic pathogenesis such as local invasion and immune escaping, thus substantially contributing to malignant metastasis and anti-cancer drug resistance. TME is composed of highly heterogeneous and dynamic components including vascular cells, immune network, adipocytes, fibroblasts, among others. Pathologically meaningful interactions occur between malignant cells and TME, also between the stromal cells within TME itself, consequently raising a challenging hurdle for a broad spectrum of anti-cancer agents to achieve the therapeutic efficacy. Herein, we sort out an updated understanding of TME biology with an emphasis on its roles in affecting clinical outcomes, and propose to better manage anti-cancer drug resistance through timely targeting the principal cellular components in TME by utilizing clinically available medicines.

Dual Targeting Autoimmunity and Cancer: From Biology to Medicine

“…Although it has been generally recognized that immune activities play complex and paradoxical roles in neoplastic pathogenesis, the dialectic viewpoint has been overwhelmed recently by the escalated focus on boosting immune responses to treat malignant diseases. It should not be ignored that chronic inflammation acts as an infamous accomplice in various phases of oncopathogenesis, particularly in solid tumors . To address this challenging issue, this article presents an updated understanding of the emerging array of molecular pathways with validated druggability, as evidenced by the targeted medicines that can treat cancer and autoimmunity simultaneously (Table ).…”

“…Representing a proinflammatory cytokine with pleiotropic effects, interleukin‐6 (IL‐6) is produced by a number of cellular lineages such as hemapoietic cells, stromal cells, and muscle cells . Upon binding of IL‐6 to the receptor (IL‐6R/CD126) or to its soluble form (sIL‐6R), resultant ligand‐receptor complex thus interacts with the gp130IL‐6 transducer (CD130), leading to gp130 dimerization and tyrosine phosphorylation.…”

“…In vivo studies have linked the IL‐6 signaling cascade to inflammatory fever, neutrophil trafficking, autoantibody production, and shifting the balance of T‐lymphocyte subsets by suppressing T‐helper 1 (Th1) cell function and inducing Th2/Th17 cell differentiation. Moreover, the IL‐6 axis was revealed to play a substantial role in driving malignant progression, metastasis, and resistance to anticancer drugs …”

“…The term tumor necrosis factor (TNF‐α) initially derived from studies showing that high concentrations of this cytokine were able to induce hemorrhagic necrosis of experimental neoplasms in animal models upon stimulation of bacterial endotoxin 4 decades ago . However, following the gene knockout‐based experiments demonstrated that TNF‐α was not essential for tumor elimination in vivo; instead, TNF‐α was revealed subsequently to be a crucial mediator of cancer‐associated inflammation, which plays a notorious role in malignant progression and metastasis . Due to the primary effects on immune cells, TNF‐α was identified as a significant cytokine that drives a systematic inflammatory response and local tissue damage in autoimmunity‐based disorders .…”

“…Upregulation of COX‐2 has been linked to activation of proinflammatory signaling pathways such as nuclear factor‐κB and STAT3, which underscores a rationale for designing COX‐2 inhibitors to treat autoimmunity‐based disorders . Moreover, the COX‐2/PGE2 axis can contribute to neoplastic progression through enhancing cancer cell survival/invasion and sustaining angiogenesis; simultaneously, this axis has been revealed to promote M2 macrophage differentiation and to induce myeloid‐derived suppressor cells, causing immune suppression in the tumor microenvironment …”