Improving therapeutic resistance: beginning with targeting the tumor microenvironment

2021 ◽  
pp. 1-25
Author(s):  
Xiao-ying Guan ◽  
Xiao-li Guan ◽  
Zuo-yi Jiao
Keyword(s):  
Tumor Microenvironment ◽  
Therapeutic Resistance

scholarly journals Hypoxic tumor microenvironment: Implications for cancer therapy

2020 ◽  
Vol 245 (13) ◽  
pp. 1073-1086
Author(s):  
Sukanya Roy ◽  
Subhashree Kumaravel ◽  
Ankith Sharma ◽  
Camille L Duran ◽  
Kayla J Bayless ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Metabolic Regulation ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Tumor Vasculature ◽  
Therapeutic Strategies ◽  
Therapeutic Resistance ◽  
Low Oxygen ◽  
Cancer Types

Hypoxia or low oxygen concentration in tumor microenvironment has widespread effects ranging from altered angiogenesis and lymphangiogenesis, tumor metabolism, growth, and therapeutic resistance in different cancer types. A large number of these effects are mediated by the transcription factor hypoxia inducible factor 1⍺ (HIF-1⍺) which is activated by hypoxia. HIF1⍺ induces glycolytic genes and reduces mitochondrial respiration rate in hypoxic tumoral regions through modulation of various cells in tumor microenvironment like cancer-associated fibroblasts. Immune evasion driven by HIF-1⍺ further contributes to enhanced survival of cancer cells. By altering drug target expression, metabolic regulation, and oxygen consumption, hypoxia leads to enhanced growth and survival of cancer cells. Tumor cells in hypoxic conditions thus attain aggressive phenotypes and become resistant to chemo- and radio- therapies resulting in higher mortality. While a number of new therapeutic strategies have succeeded in targeting hypoxia, a significant improvement of these needs a more detailed understanding of the various effects and molecular mechanisms regulated by hypoxia and its effects on modulation of the tumor vasculature. This review focuses on the chief hypoxia-driven molecular mechanisms and their impact on therapeutic resistance in tumors that drive an aggressive phenotype. Impact statement Hypoxia contributes to tumor aggressiveness and promotes growth of many solid tumors that are often resistant to conventional therapies. In order to achieve successful therapeutic strategies targeting different cancer types, it is necessary to understand the molecular mechanisms and signaling pathways that are induced by hypoxia. Aberrant tumor vasculature and alterations in cellular metabolism and drug resistance due to hypoxia further confound this problem. This review focuses on the implications of hypoxia in an inflammatory TME and its impact on the signaling and metabolic pathways regulating growth and progression of cancer, along with changes in lymphangiogenic and angiogenic mechanisms. Finally, the overarching role of hypoxia in mediating therapeutic resistance in cancers is discussed.

Abstract LB-348: Evolution of physical forces in the tumor microenvironment and implications for therapeutic resistance.

2013 ◽  
Author(s):  
Triantafyllos Stylianopoulos ◽  
John D. Martin ◽  
Saloni Jain ◽  
Matija Snuderl ◽  
Vikash P. Chauhan ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Therapeutic Resistance ◽  
Physical Forces

scholarly journals Inflammation as a Driver of Prostate Cancer Metastasis and Therapeutic Resistance

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2984 ◽  
Author(s):  
Maddison Archer ◽  
Navneet Dogra ◽  
Natasha Kyprianou
Keyword(s):  
Prostate Cancer ◽  
Tumor Microenvironment ◽  
Cancer Risk ◽  
Disease Progression ◽  
Risk Reduction ◽  
Cancer Metastasis ◽  
Prostate Gland ◽  
Prostate Cancer Risk ◽  
Therapeutic Resistance ◽  
Mesenchymal Transition

Prostate cancer is the most common malignancy among men, and progression to metastasis and the emergence of therapeutically resistant disease confers a high mortality rate. Growing evidence implicates inflammation as a driver of prostate cancer development and progression, resulting in increased cancer risk for prostate cancer. Population-based studies revealed that the use of antinflammatory drugs led to a 23% risk reduction prostate cancer occurrence, a negative association that was stronger in men who specifically used COX-2 inhibitors. Furthermore, patients that were taking aspirin had a 21% reduction in prostate cancer risk, and further, long-term users of daily low dose aspirin had a 29% prostate cancer risk reduction as compared to the controls. Environmental exposure to bacterial and viral infections, exposure to mutagenic agents, and genetic variations predispose the prostate gland to inflammation, with a coordinated elevated expression of inflammatory cytokines (IL-6, TGF-β). It is the dynamics within the tumor microenvironment that empower these cytokines to promote survival and growth of the primary tumor and facilitate disease progression by navigating the immunoregulatory network, phenotypic epithelial-mesenchymal transition (EMT), angiogenesis, anoikis resistance, and metastasis. In this review, we discuss the sources of inflammation in the prostate, the functional contribution of the critical inflammatory effectors to prostate cancer initiation and metastatic progression, and the therapeutic challenges that they impose on treatment of advanced disease and overcoming therapeutic resistance. Growing mechanistic evidence supports the significance of inflammation in localized prostate cancer, and the systemic impact of the process within the tumor microenvironment on disease progression to advanced therapeutically-resistant prostate cancer. Rigorous exploitation of the role of inflammation in prostate cancer progression to metastasis and therapeutic resistance will empower the development of precise biomarker signatures and effective targeted therapeutics to reduce the clinical burden and lethal disease in the future.

scholarly journals Tumor-Associated Neutrophils and Macrophages—Heterogenous but Not Chaotic

2020 ◽  
Vol 11 ◽  
Author(s):  
Ling Wu ◽  
Xiang H.-F. Zhang
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Immune Cells ◽  
Mutual Influence ◽  
Therapeutic Resistance ◽  
Tumor Associated Macrophages ◽  
Tumor Associated Neutrophils ◽  
Shed Light ◽  
Lines Of Evidence

Tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) have been extensively studied. Their pleotropic roles were observed in multiple steps of tumor progression and metastasis, and sometimes appeared to be inconsistent across different studies. In this review, we collectively discussed many lines of evidence supporting the mutual influence between cancer cells and TAMs/TANs. We focused on how direct interactions among these cells dictate co-evolution involving not only clonal competition of cancer cells, but also landscape shift of the entire tumor microenvironment (TME). This co-evolution may take distinct paths and contribute to the heterogeneity of cancer cells and immune cells across different tumors. A more in-depth understanding of the cancer-TAM/TAN co-evolution will shed light on the development of TME that mediates metastasis and therapeutic resistance.

Targeting Tumor-derived exosomes expressing CD73: new opportunities in the pathogenesis and treatment of cancer

2020 ◽  
Vol 20 ◽  
Author(s):  
Vajihe Taghdiri Nooshabadi ◽  
Samaneh Arab
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Cancer Development ◽  
Therapeutic Resistance ◽  
Intracellular Communication ◽  
Different Types ◽  
Therapeutic Protocols ◽  
Tumor Exosomes ◽  
Selection Of

: Tumor-derived exosomes contain biological contents such as proteins, lipids, RNA (miRNAs, mRNAs, lncRNA), and DNA for intracellular communication. Meanwhile, studies have shown the role of exosomes in cancer progression, metastasis, and therapeutic resistance. Furthermore, tumor exosomes have received growing attention due to their potential as novel therapeutic protocols for the treatment of cancers. Adenosine nucleoside, which is a derivative of ATP, is highly elevated in the tumor microenvironment by CD39 and CD73 enzymatic activity. Recently, it is distinguished that cancer cellderived exosomes carry CD39 and CD73 on their surface and may contribute to rising adenosine levels in the tumor microenvironment. In this review, we summarize the evidence of CD39/CD73-bearing exosomes and their role in cancer development, progression, invasion, angiogenesis, metastasis and their application in the selection of the appropriate strategy to treat different types of cancer.

scholarly journals Metastasis-associated fibroblasts: an emerging target for metastatic cancer

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Zimu Wang ◽  
Jiaxin Liu ◽  
Hairong Huang ◽  
Mingxiang Ye ◽  
Xinying Li ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Metastatic Cancer ◽  
Antiangiogenic Therapy ◽  
Treatment Strategies ◽  
Therapeutic Strategies ◽  
Therapeutic Resistance ◽  
Metastatic Tumors ◽  
Stromal Fibroblasts ◽  
Primary Tumors ◽  
Metastatic Sites

AbstractMetastasis suggests a poor prognosis for cancer patients, and treatment strategies for metastatic cancer are still very limited. Numerous studies have shown that cancer-associated fibroblasts (CAFs), a large component of the tumor microenvironment, contribute to tumor metastasis. Stromal fibroblasts at metastatic sites are different from CAFs within primary tumors and can be termed metastasis-associated fibroblasts (MAFs), and they also make great contributions to the establishment of metastatic lesions and the therapeutic resistance of metastatic tumors. MAFs are capable of remodeling the extracellular matrix of metastatic tumors, modulating immune cells in the tumor microenvironment, promoting angiogenesis and enhancing malignant tumor phenotypes. Thus, MAFs can help establish premetastatic niches and mediate resistance to therapeutic strategies, including immunotherapy and antiangiogenic therapy. The results of preclinical studies suggest that targeting MAFs can alleviate the progression of metastatic cancer and mitigate therapeutic resistance, indicating that MAFs are a promising target for metastatic cancer. Here, we comprehensively summarize the existing evidence on MAFs and discuss their origins, generation, functions and related therapeutic strategies in an effort to provide a better understanding of MAFs and offer treatment perspectives for metastatic cancer.

scholarly journals SFRP2 augments WNT16B signaling to promote therapeutic resistance in the damaged tumor microenvironment

Oncogene ◽  
2016 ◽  
Vol 35 (33) ◽  
pp. 4321-4334 ◽  
Author(s):  
Y Sun ◽  
D Zhu ◽  
F Chen ◽  
M Qian ◽  
H Wei ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Therapeutic Resistance

scholarly journals Combined MEK and STAT3 inhibition reprograms the tumor microenvironment to overcome immunotherapy resistance in pancreatic cancer

2021 ◽  
Author(s):  
Jashodeep Datta ◽  
Purushottam Lamichhane ◽  
Xizi Dai ◽  
Siddharth Mehra ◽  
Austin R. Dosch ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Ductal Adenocarcinoma ◽  
Therapeutic Resistance ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Immune Microenvironment ◽  
Adaptive Immune ◽  
Cell Enrichment ◽  
Immune Exclusion ◽  
Stat3 Inhibition

ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is characterized by immune exclusion, stromal desmoplasia, and resistance to immune checkpoint inhibition (ICI). We have previously demonstrated that reciprocally activated RAS/RAF/MEK/ERK and JAK/STAT3 pathways mediate therapeutic resistance, while combined MEK and STAT3 inhibition (MEKi/STAT3i) overcomes this resistance in PDAC. Herein, we show that combined MEKi/STAT3i alters stromal architecture and remodels the tumor-infiltrating innate and adaptive immune compartments by downregulating immunosuppressive myeloid populations and promoting T-cell enrichment and activation in Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) mice. MEKi/STAT3i-mediated reprogramming of the PDAC tumor microenvironment primes tumor-infiltrating CD8+ T-cells for PD-1 blockade to augment their activation and functional cytotoxicity. As such, the addition of MEKi/STAT3i to PD-1 blockade dramatically inhibits tumor growth and prolongs survival, overcoming resistance to ICI, in PKT mice. Importantly, treatment of a patient with chemotherapy-refractory metastatic PDAC with MEKi (Trametinib), STAT3i (Ruxolitinib), and PD-1 inhibitor (Nivolumab) was not only well-tolerated but also yielded significant clinical benefit.SignificanceThese data uncover a novel paradigm in which combined MEKi/STAT3i reprograms the stromal and immune microenvironment to overcome immunotherapy resistance in PDAC. The clinical efficacy of combined MEKi, STAT3i, and anti-PD1 treatment in chemotherapy-refractory PDAC provides encouraging signals for its translatability, and is being currently pursued in a clinical trial.

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