Normalization of tumor microvasculature basing on targeting and modulation of tumor microenvironment

AbstractThe tumor vessel network has been investigated as a precursor of an inhospitable tumor microenvironment, including its repercussions in tumor perfusion, oxygenation, interstitial fluid pressure, pH, and immune response. Dysfunctional tumor vasculature leads to the extravasation of blood to the interstitial space, hindering proper perfusion and causing interstitial hypertension. Consequently, the inadequate delivery of oxygen and clearance of by-products of metabolism promote the development of intratumoral hypoxia and acidification, hampering the action of immune cells and resulting in more aggressive tumors. Thus, pharmacological strategies targeting tumor vasculature were developed, but the overall outcome was not satisfactory due to its transient nature and the higher risk of hypoxia and metastasis. Therefore, physical exercise emerged as a potential favorable modulator of tumor vasculature, improving intratumoral vascularization and perfusion. Indeed, it seems that regular exercise practice is associated with lasting tumor vascular maturity, reduced vascular resistance, and increased vascular conductance. Higher vascular conductance reduces intratumoral hypoxia and increases the accessibility of circulating immune cells to the tumor milieu, inhibiting tumor development and improving cancer treatment. The present paper describes the implications of abnormal vasculature on the tumor microenvironment and the underlying mechanisms promoted by regular physical exercise for the re-establishment of more physiological tumor vasculature.

Tumor Microenvironment

Medicina ◽

10.3390/medicina56010015 ◽

2019 ◽

Vol 56 (1) ◽

pp. 15 ◽

Cited By ~ 16

Author(s):

Borros Arneth

Keyword(s):

Tumor Microenvironment ◽

Tumor Development ◽

Tumor Vasculature ◽

Cell Types ◽

Cancer Associated Fibroblasts ◽

Positive Health ◽

Positive Health Outcomes ◽

Uncontrolled Cell Proliferation ◽

Significant Attention ◽

Malignant Behavior

Background and Objectives: The tumor microenvironment has been widely implicated in tumorigenesis because it harbors tumor cells that interact with surrounding cells through the circulatory and lymphatic systems to influence the development and progression of cancer. In addition, nonmalignant cells in the tumor microenvironment play critical roles in all the stages of carcinogenesis by stimulating and facilitating uncontrolled cell proliferation. Aim: This study aims to explore the concept of the tumor microenvironment by conducting a critical review of previous studies on the topic. Materials and Methods: This review relies on evidence presented in previous studies related to the topic. The articles included in this review were obtained from different medical and health databases. Results and Discussion: The tumor microenvironment has received significant attention in the cancer literature, with a particular focus on its role in tumor development and progression. Previous studies have identified various components of the tumor microenvironment that influence malignant behavior and progression. In addition to malignant cells, adipocytes, fibroblasts, tumor vasculature, lymphocytes, dendritic cells, and cancer-associated fibroblasts are present in the tumor microenvironment. Each of these cell types has unique immunological capabilities that determine whether the tumor will survive and affect neighboring cells. Conclusion: The tumor microenvironment harbors cancer stem cells and other molecules that contribute to tumor development and progression. Consequently, targeting and manipulating the cells and factors in the tumor microenvironment during cancer treatment can help control malignancies and achieve positive health outcomes.

Targeting the Tumor Microenvironment by Intervention in Interleukin-1 Biology

Current Pharmaceutical Design ◽

10.2174/1381612823666170613080919 ◽

2017 ◽

Vol 23 (32) ◽

pp. 4893-4905 ◽

Cited By ~ 7

Author(s):

Elena Voronov ◽

Ron N. Apte

Keyword(s):

Tumor Microenvironment ◽

Cancer Patients ◽

Tumor Immunity ◽

Biological Activities ◽

Interleukin 1 ◽

Tumor Development ◽

Tumor Treatment ◽

Tumor Invasiveness ◽

First Line Therapy ◽

Inflammatory Component

The importance of anti-tumor immunity in the outcome of cancer is now unequivocally established and recent achivements in the field have stimulated the development of new immunotherapeutical approaches. In invasive tumors, widespread inflammation promotes invasiveness and concomitantly also inhibits anti-tumor immune responses. We suggest that efficient tumor treatment should target both the malignant cells and the tumor microenvironment. Interleukin-1 (IL-1) is a pro-inflammatory as well as an immunostimulatory cytokine that is abundant in the tumor microenvironment. Manipulation of IL-1 can thus serve as an immunotherapeutical approach to reduce inflammation/immunosuppression and thus enhance anti-tumor immunity. The two major IL-1 agonistic molecules are IL-1α and IL-1β, which bind to the same IL-1 signaling receptor and induce the same array of biological activities. The IL-1 receptor antagonist (IL-Ra) is a physiological inhibitor of IL-1 that binds to its receptor without transmition of activation signals and thus serves as a decoy target. We have demonstrated that IL-1α and IL-1β are different in terms of the producing cells and their compartmentalization and the amount. IL-1α is mainly expressed intracellularly, in the cytosol, in the nucleus or exposed on the cell membrane, however, it is rarely secreted. IL-1β is active only as a secreted molecule that is mainly produced by activated myeloid cells. We have shown different functions of IL-1α and IL-1β in the malignant process. Thus, in its membrane- associated form, IL-1α is mainly immunostimulatory, while IL-1β that is secreted into the tumor microenvironment is mainly pro-inflammatory and promotes tumorigenesis, tumor invasiveness and immunosuppression. These distinct functions of the IL-1 agonistic molecules are mainly manifested in early stages of tumor development and the patterns of their expression dictate the direction of the malignant process. Here, we suggest that IL-1 modulation can serve as an effective mean to tilt the balance between inflammation and immunity in tumor sites, towards the latter. Different agents that neutralize IL-1, mainly the IL-Ra and specific antibodies, exist. They are safe and FDA-approved. The IL-1Ra has been widely and successfully used in patients with Rheumatoid arthritis, autoinflammatory diseases and various other diseases that have an inflammatory component. Here, we provide the rationale and experimental evidence for the use of anti-IL-1 agents in cancer patients, following first line therapy to debulk the major tumor's mass. The considerations and constraints of using anti-IL-1 treatments in cancer are also discussed. We hope that this review will stimulate studies that will fasten the application of IL-1 neutralization at the bedside of cancer patients.

Hypoxic tumor microenvironment: Implications for cancer therapy

Experimental Biology and Medicine ◽

10.1177/1535370220934038 ◽

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.

CXCL12 and Its Isoforms: Different Roles in Pancreatic Cancer?

Journal of Oncology ◽

10.1155/2019/9681698 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 4

Author(s):

Alessandra Righetti ◽

Matteo Giulietti ◽

Berina Šabanović ◽

Giulia Occhipinti ◽

Giovanni Principato ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Microenvironment ◽

Stromal Cells ◽

Tumor Invasion ◽

Epithelial To Mesenchymal Transition ◽

Current Knowledge ◽

Tumor Development ◽

Physiological Role ◽

Mesenchymal Transition ◽

Splicing Isoforms

CXCL12 is a chemokine that acts through CXCR4 and ACKR3 receptors and plays a physiological role in embryogenesis and haematopoiesis. It has an important role also in tumor development, since it is released by stromal cells of tumor microenvironment and alters the behavior of cancer cells. Many studies investigated the roles of CXCL12 in order to understand if it has an anti- or protumor role. In particular, it seems to promote tumor invasion, proliferation, angiogenesis, epithelial to mesenchymal transition (EMT), and metastasis in pancreatic cancer. Nevertheless, some evidence shows opposite functions; therefore research on CXCL12 is still ongoing. These discrepancies could be due to the presence of at least six CXCL12 splicing isoforms, each with different roles. Interestingly, three out of six variants have the highest levels of expression in the pancreas. Here, we report the current knowledge about the functions of this chemokine and then focus on pancreatic cancer. Moreover, we discuss the methods applied in recent studies in order to understand if they took into account the existence of the CXCL12 isoforms.

730 Hypoxia reduction in tandem with anti-angiogenic therapy remodels the PDAC microenvironment and potentiates CD40 agonist therapy

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.730 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A759-A759

Author(s):

Arthur Liu ◽

Michael Curran

Keyword(s):

Prostate Cancer ◽

Pancreatic Cancer ◽

T Cell ◽

Tumor Microenvironment ◽

Cell Function ◽

Tumor Vasculature ◽

Cd8 T Cell ◽

Agonist Therapy ◽

Angiogenic Therapy ◽

T Cell Infiltration

BackgroundThe majority of patients with pancreatic ductal adenocarcinoma (PDAC) fail to derive any durable responses from single agent immune checkpoint blockade therapy. This refractory state originates from PDAC's unique tumor microenvironment that is densely populated by immunosuppressive myeloid cells while excluding most antitumor CD8 T cells.1 In addition, PDAC is highly hypoxic and exhibits poor vascularity, both qualities which further limit antitumor immunity.2 3 We showed that the hypoxia-activated prodrug TH-302 (Evofosfamide) potentiates immunotherapy responses.4 Mechanistically, TH-302 decreases intratumoral hypoxia and initiates normalization of the tumor vasculature. While TH-302 facilitates a cellular remodeling process that diminishes tumor hypoxia, the nature of the vascular remodeling involved remains unknown, as do the downstream consequences for the composition of the tumor microenvironment and responsiveness to immunotherapy. We hypothesized that anti-angiogenic therapy and Evofosfamide might cooperate to normalize tumor vasculature and diminish hypoxia.MethodsTH-302 and a vascular endothelial growth factor receptor-2 (VEGFR-2) blocking antibody were used to treat several syngeneic murine models, including orthotopic pancreatic cancer and a transplantable model of prostate cancer. Immunofluorescence and flow cytometry were used to assess intratumoral hypoxia, vessel normalization, and tumor immune infiltrate.ResultsWe find that anti-VEGFR-2 (DC101) in combination with TH-302 demonstrates a cooperative benefit to combat both orthotopically implanted pancreatic cancer and transplantable prostate cancer. Combination therapy reduces intratumoral hypoxia, leads to pruning of the tumor vasculature, and increases the infiltration of endothelial cells into hypoxic regions. Across models, the combination of DC101 and TH-302 significantly enhance CD8 T cell function and limits their exhausted state. At the same time, tumor associated macrophages exhibit decreased expression of M2-like features. Similar to other anti-angiogenic therapies, combination DC101 and TH-302 leads to an increased frequency of PD-L1 expressing cells. Concurrent anti-PD-1 failed to provide any additional therapeutic benefit, which in part may be due poor CD8 T cell infiltration. Instead, we find that CD40 agonist therapy is improved when combined with TH-302 and DC101.ConclusionsTH-302 and DC101 utilize unique yet complementary mechanisms to improve the survival of mice challenged with pancreatic or prostate tumors. This combination relieves hypoxia and simultaneously reinvigorates T cell function and reduces macrophage mediated immunosuppression. In this setting, CD40 agonist therapy provides an additive benefit in prolonging mouse survival. Put together, these data indicate that targeted hypoxia reduction with anti-angiogenic therapy remodels the tumor microenvironment and enhances immunotherapy responses in PDAC.ReferencesBear AS, Vonderheide RH, O'Hara MH. Challenges and opportunities for pancreatic cancer immunotherapy. Cancer Cell. 2020;38(6):788–802. doi: 10.1016/j.ccell.2020.08.004. Epub 2020 Sep 17. PMID: 32946773; PMCID: PMC7738380.Koong AC, Mehta VK, Le QT, Fisher GA, Terris DJ, Brown JM, Bastidas AJ, Vierra M. Pancreatic tumors show high levels of hypoxia. Int J Radiat Oncol Biol Phys 2000;48(4):919–22. doi: 10.1016/s0360-3016(00)00803-8. PMID: 11072146.Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, Frese KK, Denicola G, Feig C, Combs C, Winter SP, Ireland-Zecchini H, Reichelt S, Howat WJ, Chang A, Dhara M, Wang L, Rückert F, Grützmann R, Pilarsky C, Izeradjene K, Hingorani SR, Huang P, Davies SE, Plunkett W, Egorin M, Hruban RH, Whitebread N, McGovern K, Adams J, Iacobuzio-Donahue C, Griffiths J, Tuveson DA. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009;324(5933):1457–61. doi: 10.1126/science.1171362. Epub 2009 May 21. PMID: 19460966; PMCID: PMC2998180.Jayaprakash P, Ai M, Liu A, Budhani P, Bartkowiak T, Sheng J, Ager C, Nicholas C, Jaiswal AR, Sun Y, Shah K, Balasubramanyam S, Li N, Wang G, Ning J, Zal A, Zal T, Curran MA. Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy. J Clin Invest 2018;128(11):5137–5149. doi: 10.1172/JCI96268. Epub 2018 Oct 15. PMID: 30188869; PMCID: PMC6205399.

Numerical Investigation of Drug Transport from Blood Vessels to Tumor Tissue Using a Tumor-Vasculature-on-a-Chip

10.1101/652099 ◽

2019 ◽

Author(s):

Wei Li ◽

Hao-Fei Wang ◽

Zhi-Yong Li ◽

Tong Wang ◽

Chun-Xia Zhao

Keyword(s):

Tumor Microenvironment ◽

Blood Vessel ◽

Drug Concentration ◽

Tumor Size ◽

Drug Transport ◽

Tumor Tissue ◽

Transport Model ◽

Temporal Structure ◽

Drug Distribution ◽

Tumor Vasculature

AbstractThe delivery of adequate concentration of anticancer drugs to tumor site is critical to achieve effective therapeutic treatment, but it is challenging to experimentally observe drug transport and investigate the spatial distribution of the drug in tumor microenvironment. In this study, we investigated the drug transport from a blood vessel to tumor tissue, and explored the effect of tumor size, tumor numbers and positioning on drug concentration distribution using a numerical method in combination with a microfluidic Tumor-Vasculature-on-a-Chip (TVOC) model. The TVOC model is composed of a vessel channel, a tumor channel sandwiched with a porous membrane. A species transport model based on computational fluid dynamics was adapted to investigate drug transport. The numerical simulation was firstly validated using experimental data, and then used to analyse the spatial-temporal structure of the flow, and to investigate the effect of tumor size and positioning on drug transport and drug concentration heterogeneity. We found the drug concentration surrounding the tumor is highly heterogeneous, with the most downstream point the most difficult for drugs to transport and the nearest point to the blood vessel the easiest. Moreover, tumor size and positioning contribute significantly to this drug concentration heterogeneity on tumor surface, which is dramatically augmented in large and downstream-positioned tumors. These studies established the relationship between solid tumor size/positioning and drug concentration heterogeneity in the tumor microenvironment, which could help to understand heterogenous drug distribution in tumor microenvironment.

Remodeling tumor microenvironment by liposomal co-delivery of DMXAA and simvastatin inhibits malignant melanoma progression

10.1101/2021.04.26.441259 ◽

2021 ◽

Author(s):

Valentin Florian Rauca ◽

Laura Patras ◽

Lavinia Luput ◽

Emilia Licarete ◽

Vlad Alexandru Toma ◽

...

Keyword(s):

Tumor Microenvironment ◽

Hypoxia Inducible Factor ◽

Tumor Development ◽

Novel Therapy ◽

Drug Induced ◽

Angiogenic Therapy ◽

Melanoma Model ◽

M1 Phenotype

Anti-angiogenic therapies for melanoma have not yet been translated into meaningful clinical benefit for patients, due to development of drug-induced resistance in cancer cells, mainly caused by hypoxia-inducible factor 1α (HIF-1α) overexpression and enhanced oxidative stress mediated by tumor-associated macrophages (TAMs). Our previous study demonstrated synergistic antitumor actions of simvastatin (SIM) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) on an in vitro melanoma model via suppression of the aggressive phenotype of melanoma cells and inhibition of TAMs-mediated angiogenesis. Therefore, we took the advantage of long circulating liposomes (LCL) superior tumor targeting capacity to efficiently deliver SIM and DMXAA to B16.F10 melanoma in vivo, with the final aim of improving the outcome of the anti-angiogenic therapy. Thus, we assessed the effects of this novel combined tumor-targeted treatment on s.c. B16.F10 murine melanoma growth and on the production of critical markers involved in tumor development and progression. Our results showed that the combined liposomal therapy inhibited almost totally the growth of melanoma tumors, due to the enhancement of anti-angiogenic effects of LCL-DMXAA by LCL-SIM and induction of a pro-apoptotic state in the tumor microenvironment (TME). These effects were favoured by the partial re-education of TAMs towards a M1 phenotype and maintained via suppression of major invasion and metastasis promoters (HIF-1α, pAP-1 c-Jun, and MMPs). Thus, this novel therapy holds the potential to remodel the tumor microenvironment, by suppressing its most important malignant biological capabilities.

The Roles of Stroma-Derived Chemokine in Different Stages of Cancer Metastases

Frontiers in Immunology ◽

10.3389/fimmu.2020.598532 ◽

2020 ◽

Vol 11 ◽

Author(s):

Shahid Hussain ◽

Bo Peng ◽

Mathew Cherian ◽

Jonathan W. Song ◽

Dinesh K. Ahirwar ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tumor Cells ◽

Cancer Progression ◽

Tumor Development ◽

Inflammatory Cells ◽

Host Cells ◽

Metastatic Niche ◽

Cancer Pathogenesis ◽

Cancer Metastases ◽

Cellular Components

The intricate interplay between malignant cells and host cellular and non-cellular components play crucial role in different stages of tumor development, progression, and metastases. Tumor and stromal cells communicate to each other through receptors such as integrins and secretion of signaling molecules like growth factors, cytokines, chemokines and inflammatory mediators. Chemokines mediated signaling pathways have emerged as major mechanisms underlying multifaceted roles played by host cells during tumor progression. In response to tumor stimuli, host cells-derived chemokines further activates signaling cascades that support the ability of tumor cells to invade surrounding basement membrane and extra-cellular matrix. The host-derived chemokines act on endothelial cells to increase their permeability and facilitate tumor cells intravasation and extravasation. The tumor cells-host neutrophils interaction within the vasculature initiates chemokines driven recruitment of inflammatory cells that protects circulatory tumor cells from immune attack. Chemokines secreted by tumor cells and stromal immune and non-immune cells within the tumor microenvironment enter the circulation and are responsible for formation of a “pre-metastatic niche” like a “soil” in distant organs whereby circulating tumor cells “seed’ and colonize, leading to formation of metastatic foci. Given the importance of host derived chemokines in cancer progression and metastases several drugs like Mogamulizumab, Plerixafor, Repertaxin among others are part of ongoing clinical trial which target chemokines and their receptors against cancer pathogenesis. In this review, we focus on recent advances in understanding the complexity of chemokines network in tumor microenvironment, with an emphasis on chemokines secreted from host cells. We especially summarize the role of host-derived chemokines in different stages of metastases, including invasion, dissemination, migration into the vasculature, and seeding into the pre-metastatic niche. We finally provide a brief description of prospective drugs that target chemokines in different clinical trials against cancer.

Abstract 1520: Estrogen modulates angiogenic factors of thyroid tumor microenvironment

10.1158/1538-7445.am2012-1520 ◽

2012 ◽

Author(s):

Shilpi Rajoria ◽

Andrea George ◽

Robert Suriano ◽

Edward J. Shin ◽

Jan Geliebter ◽

...

Keyword(s):

Tumor Microenvironment ◽

Thyroid Tumor ◽

Angiogenic Factors