Tumor microenvironment - Knowledge (XXG)

539: 531: 547: 388: 237: 33: 329: 507:, sustained angiogenesis, limitless replication potential, and tissue invasion. In cancer, changes in the ECM dynamics lead to changes in composition, density, and mechanical properties, affecting tumor aggressiveness and response to therapy. Research suggests that both pro- and anti-tumorigenic effects occurs during ECM remodeling. In early tumor formation, stromal cells produce excess ECM proteins, causing the tissue around the tumor to stiffen. Some of the contributing factors to tumor stiffness is increased 184:, where new blood vessels emerge from pre-existing vasculature. The blood vessel formed in the tumor environment often does not mature properly, and as a result the vasculature formed in the tumor microenvironment differs from that of normal tissue. The blood vessels formed are often "leaky" and tortuous, with a compromised blood flow. As tumors cannot grow large without proper vasculature, sustained angiogenesis is therefore considered one of the hallmarks of cancer. 496: 68:. Mutual interaction between cancer cells and the different components of the tumor microenvironment support its growth and invasion in healthy tissues which correlates with tumor resistance to current treatments and poor prognosis. The tumor microenvironment is in constant change because of the tumor's ability to influence the microenvironment by releasing extracellular signals, promoting 643:

block metastasis, as natural killer cells are most efficient at killing cancer cells outside of the tumor microenvironment. Tumor-infiltrating lymphocytes have been used in therapeutic treatments, where lab-amplificated immune cells are transferred to cancer patients to help their immune system fight the cancer. This treatment has seen success in solid tumors such as melanoma.

339:(CAFs) are a heterogenous group of activated fibroblasts central to the reactive stroma within the tumor microenvironment. The precise definition of CAFs remains challenging due to variations in cellular origins and expression markers. However, evidence suggests CAFs originate from activated resident fibroblasts, bone marrow-derived 682:(IL-2), and by cross-presenting tumor antigens. Tregs are, as opposed to CD8+, tumor promoting. They secrete tumor growth factors, and indirectly support cancer survival by interacting with endothelial cells and carcinoma associated fibroblasts. Tregs also have immunosuppressive mechanisms that can make CD8+ cells less effective. 366:; one that promotes tumor growth and another that inhibits it, with the former being more common and contributing to tumor development and therapy resistance through various mechanisms. Various subpopulations of CAFs have been identified across different cancer types. In breast cancer, for example, studies using 966:

as well as replicate rapidly and homogenously, making them potentially very effective as a cancer-therapy. Since the tumor microenvironment has several barriers that limit the ability of CAR T cells to infiltrate the tumor, several strategies have been developed to address this. Localized delivery of

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Tumor-infiltrating lymphocytes are lymphocytes, including T cells, B cells and natural killer cells, that penetrate the tumor and have the ability to recognize and kill cancer cells. A high concentration is generally positively correlated with good prognosis (802). This type of immune cells can also

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that regulate functions and mechanical properties. However, in tumors, the ECM plays an important role in shaping the tumor microenvironment and influences cancer progression, metastasis, and therapeutic response. This process is called extracellular matrix remodeling and is characterized by changes

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Experiments in mice have mainly shown that tumor-associated neutrophils exhibit tumor-promoting functions, but a smaller number of studies show that neutrophils can also inhibit tumor growth. Tumor associated neutrophils can be divided into N1- and N2-polarized neutrophils. N1-polarized neutrophils

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from tumor cells. Stromal cells contribute to tumor initiation, progression and drug resistance, and the stroma is known to evolve as the tumor develops. Understanding the interactions between cancer cells and stromal cells is essential for developing effective cancer treatments. Alterations in the

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Hypoxia causes the upregulation of hypoxia induced factors (HIFs), which are transcription factors that decides how cells respond to a lack of oxygen. HIFs induces the transcription of thousands of genes, some of which induces angiogenesis or furthers metastasis, leading, for instance, to increased

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genetic variants can significantly influence the composition of the tumor microenvironment. These germline variants affect the number of infiltrating CD8 T cells and regulatory T cells within tumors, thereby impacting immune evasion and responses to immunotherapy. Notably, studies published in the

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analysis and single-cell RNA sequencing have shed more light on the diverse characteristics of CAFs, revealing distinct and sometimes contradictory functions. Their functions appear to be context dependent. This diversity in stomal composition not only shapes the tumor microenvironment, but also

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T cells must replicate after arriving at the tumor site to effectively kill the cancer cells, survive hostile elements and migrate through the stroma to the cancer cells. This is affected by the tumor microenvironment. The draining lymph nodes are the likely location for cancer specific T cell

460:. The transmission of signals from the ECM to the cell interior involves various pathways. One primary way is direct transduction mediated by transmembrane proteins like integrins. Integrins is the most studied ECM binding receptor and mediate ECM remodeling and regular cellular processes like 593:

activation allows for the smoldering inflammation seen in cancer. Unlike normal macrophages, tumor-associated macrophages lack cytotoxic activity. Monocyte derived macrophages are divided into inflammatory M1-polarized macrophages and anti-inflammatory M2-polarized macrophages. M1-polarized

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Tumor-associated immune cells can be tumor-antagonizing or tumor-promoting, meaning that they can suppress or promote tumor growth. Because of the effects of hypoxia, the anti-tumor abilities of many tumor-antagonizing immune cells, such as cytotoxic T cells and natural killer cells, become

624:. Neutrophils can accumulate in tumors and in some cancers, such as lung adenocarcinoma, their abundance at the tumor site is associated with worsened disease prognosis. Neutrophil numbers (and myeloid cell precursors) in the blood can be increased in some patients with solid tumors. 113:

factors of the vascular connection, with tumor cells more likely to be trapped in the first connected organ. This viewpoint suggested that certain properties or mutations within cancer cells might dictate their metastatic potential, independent of the surrounding tissue environment.

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of a particular type of cancer ("the seed") often metastasizes to certain sites ("the soil") based on the similarity of the original and secondary tumor sites. In other words, just as seeds need fertile soil to grow, cancer cells require a supportive microenvironment to metastasize.

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The enhanced permeability and retention effect is the observation that the vasculature of tumors tend to accumulate macromolecules in the blood stream to a greater extent than in normal tissue. This is due to the "leaky" nature of the vasculature around tumors, and a lacking

96:'s "seed and soil" theory introduced the important role of TME in cancer metastasis, highlighting the intricate relationship between tumors and their surrounding microenvironment. The theory indicated that cancer cells have tendencies when spreading. Paget proposed that the 511:

and acid deposition. Additionally, the restructured ECM and its degradation fragments (matrikines) impacts signaling pathways via cell-surface receptor interactions, leading to dysregulated stromal cell behavior and the emergence of an oncogenic microenvironment.

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Targeting CAF has emerged as a promising strategy for improving cancer treatment, but the research faces several challenges. These include gaps in our understanding of CAF origins and their diverse functions, some of which may be helpful in combating tumors.

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CAFs are one of the most common components of the tumor stroma and are particularly found in the interstitial spaces of breast, prostate, and pancreatic cancer. They interact with cancer cells by secreting a variety of extracellular matrix components or

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macrophages phagocytize tumor cells and are considered tumor-antagonizing. M2-polarized macrophages are, on the other hand, tumor-promoting, because they promote tumor progression by suppressing immunosurveillance, aiding angiogenesis by secreting

214:. The permeable vasculature allows for easier delivery of therapeutic drugs to the tumor, and the lacking lymphatic vessels contribute to an increased retention. The permeable vasculature is thought to have several causes, including insufficient 268:

pathways. This genetic instability leads to a high number of mutated cells, and is associated with cancer progression. Periods of mild and acute hypoxia and reoxygenation can lead cancer cells to adapt and grow into more aggressive phenotypes.

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stroma, including the activation of fibroblasts into carcinoma-associated fibroblasts (CAFs) and remodeling of the extracellular matrix (ECM), are recognized as important in cancer progression and potential targets for therapy and diagnosis.

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Unezaki S, Maruyama K, Hosoda JI, Nagae I, Koyanagi Y, Nakata M, et al. (22 November 1996). "Direct measurement of the extravasation of polyethyleneglycol-coated liposomes into solid tumor tissue by in vivo fluorescence microscopy".

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Zhang W, Wang L, Zhou D, Cui Q, Zhao D, Wu Y (January 2011). "Expression of tumor-associated macrophages and vascular endothelial growth factor correlates with poor prognosis of peripheral T-cell lymphoma, not otherwise specified".

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Cancer is a complex disease involving both tumor cells and surrounding stromal cells. In cancer biology, the stroma is defined as the nonmalignant cells found in the supportive tissue surrounding tumors. These cells include

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T cells reach tumor sites via the vascular system, where the tumor microenvironment appears to preferentially recruit other immune cells over T cells. One such discriminating mechanism is the release of cell-type specific

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formulated a complementary hypothesis in the 1970s, where he proposed that while the mechanical aspects of blood flow is important, metastatic colonization specifically targets certain organs, known as organotropism.

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and immune-suppressive properties. However, their cytotoxic activity was found to be lower compared to lymphocytes from distant sites, likely due to the overall immunosuppressive state in tumor-bearing individuals.

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A tumor's vasculature is important to its growth, as blood vessels deliver oxygen, nutrients, and growth factors to the tumor. Tumors smaller than 1–2 mm in diameter are delivered oxygen and nutrients through

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challenged Paget's theory with his own perspective on cancer metastasis. Ewing proposed that the ability of cancer cells to metastasize was primarily influenced by mechanical mechanisms such as anatomical and

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vehicles (~20–200 nm in diameter) can transport drugs and other therapeutic molecules. These therapies can be targeted to selectively extravasate through tumor vasculature. These efforts include protein

674:(Tregs). CD8+ cells are tumor-antagonizing cells that recognize tumor antigens and targets cancer cells for destruction. In addition, CD8+ cells slow tumor progression and suppress angiogenesis by releasing 598:(VEGF) and remodeling the extracellular matrix. The tumor microenvironment promotes the M2-polarized macrophages, and an increased amount of tumor-associated macrophages is associated with worse prognosis. 943:(PTKs). This show promise in modulating the tumor microenvironment, resulting in cancer regression. Understanding how TKIs modulates the tumor microenvironment may offer another form of cancer treatment. 3960:

Zhang BC, Gao J, Wang J, Rao ZG, Wang BC, Gao JF (December 2011). "Tumor-associated macrophages infiltration is associated with peritumoral lymphangiogenesis and poor prognosis in lung adenocarcinoma".

355:, which is important in regulating the biological behavior of tumors. These regulations are particularly important for tumor development and influence cancer cell growth, invasion, inflammation, and 628:

accumulate in the tumor in its early stages and support with tumor cell death. In later stages N2-polarized neutrophils promotes angiogenesis by secreting vascular endothelial growth factor (VEGF).

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into chemical signals. Integrins can sense differences between simple, rigid two-dimensional surfaces and complex, malleable three-dimensional environments, altering cellular signaling accordingly.

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Stromal cells within the tumor microenvironment represent an important cellular component in cancer development, influencing tumor metabolism, growth, metastasis, immune evasion, and resistance to

698:(FasL) in the vasculature of ovarian, colon, prostate, breast, bladder and renal tumors. Tumors with a high expression of FasL has been shown to contain an abundancy of Tregs, but few CD8+ cells. 285:". HIFs also regulate immune cells, and an increased expression can lead to the inactivation of anti-tumor functions. This furthers the survival of tumor cells and hinders anti-tumor treatment. 646:

Tumor-infiltrating lymphocytes can become tumor-promoting due to the immunosuppressive mechanisms of the tumor microenvironment. Cancer cells induce apoptosis of activated T cells by secreting

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While ECM remodeling is tightly regulated under normal physiological conditions, it also modulates many of the tumor cell behaviors associated with cancer progression. This includes evasion of

487:. These receptors interact with various ECM components and create diverse cellular processes that contribute both to normal physiological functions and pathological conditions like cancer. 5072:

Feng Y, Liao Z, Zhang H, Xie X, You F, Liao X, et al. (January 2023). "Emerging nanomedicines strategies focused on tumor microenvironment against cancer recurrence and metastasis".

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and cell-matrix alterations. ECM remodeling involves dynamic alterations in ECM composition, organization, and biomechanical properties. ECM remodeling is induced by factors such as

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of oxygen is below 5 mmHg in over 50% of locally advanced solid tumors, compared to venous blood which has a partial pressure of oxygen at 40-60 mmHg. A hypoxic environment leads to

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Lei X, Lei Y, Li JK, Du WX, Li RG, Yang J, et al. (2020-02-01). "Immune cells within the tumor microenvironment: Biological functions and roles in cancer immunotherapy".

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Korneev KV, Atretkhany KN, Drutskaya MS, Grivennikov SI, Kuprash DV, Nedospasov SA (January 2017). "TLR-signaling and proinflammatory cytokines as drivers of tumorigenesis".

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cell migration and matrix remodeling. An increased HIF expression can lead tumor cells to shift their metabolism from aerobic to anaerobic, where they obtain energy through

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Danhier F, Feron O, Préat V (December 2010). "To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery".

827:, the nanocarrier size (10–100 nm, with greater retention in tumors seen in using larger nanocarriers) and charge (anionic or neutral) must be considered. 546: 5194:

Lilavivat S, Sardar D, Jana S, Thomas GC, Woycechowsky KJ (August 2012). "In vivo encapsulation of nucleic acids using an engineered nonviral protein capsid".

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Freedman LP, Gibson MC, Ethier SP, Soule HR, Neve RM, Reid YA (June 2015). "Reproducibility: changing the policies and culture of cell line authentication".

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in the microenvironment and is present in all tissue. The ECM is a highly dynamic structure and is essential for tissue development, repair, support, and

387: 204: 4199:"Prognostic value of pretreatment circulating neutrophils, monocytes, and lymphocytes in oropharyngeal cancer stratified by human papillomavirus status" 3742:

Mathias RA, Gopal SK, Simpson RJ (January 2013). "Contribution of cells undergoing epithelial-mesenchymal transition to the tumour microenvironment".

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Component of the tumor microenvironment (TME). The tumor microenvironment is a complex system of various tumor cells, stromal cells, and immune cells.

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inhibited. Tumor-promoting immune cells such as regulatory T cells and myeloid derived suppressor cells will, on the other hand, become upregulated.

156:. In larger tumors the center becomes too far away from the existing blood supply, leading the tumor microenvironment to become hypoxic and acidic. 3820:"A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation)" 917:

are potent, specific and target abnormal kinases while minimizing toxicity. Kinase inhibitors have expanded treatment options for various cancers.

1469: 281:, which decreases the pH in the microenvironment from a neutral and healthy 7.35-7.45 to an acidic 6.3-7.0. This phenomenon is described as the " 5495:

Mansour MA, Caputo VS, Aleem E (2021-11-01). "Highlights on selected growth factors and their receptors as promising anticancer drug targets".

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suggested improvement of CAR T cell trafficking. As this therapy expands to other diseases, managing its unique toxicity profile, including

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Larsen M, Artym VV, Green JA, Yamada KM (2006-10-01). "The matrix reorganized: extracellular matrix remodeling and integrin signaling".

992: 852: 595: 575: 177: 4682: 806:. These approaches aimed to improve anti-tumor effects and sensitize other therapies. Researchers have discovered that the use of 936: 559: 4462:"Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils" 3439:"Tumor Extracellular Matrix Remodeling: New Perspectives as a Circulating Tool in the Diagnosis and Prognosis of Solid Tumors" 637: 370:

have revealed distinct phenotypes, including vascular CAFs, matrix CAFs, cycling CAFs, and developmental CAFs. Studies using

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Alasvand N, Urbanska AM, Rahmati M, Saeidifar M, Gungor-Ozkerim PS, Sefat F, et al. (2017-01-01), Grumezescu AM (ed.),

735:. 3D tumor models have been developed as a more spatially representative model of the TME. Spheroid cultures, scaffolds and 731:

have been long used in order to study various tumors. They are quick to set up and inexpensive, but simplistic and prone to

236: 5637:"Optimization of IL13Rα2-Targeted Chimeric Antigen Receptor T Cells for Improved Anti-tumor Efficacy against Glioblastoma" 879: 3498:"Cancer cells' ability to mechanically adjust to extracellular matrix stiffness correlates with their invasive potential" 868: 856: 795: 336: 860: 803: 5356:"Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects" 5033:"Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response" 650:

containing death ligands such as FasL and TRAIL, and via the same method, turn off the normal cytotoxic response of

4248:"Prognostic value of monocyte and neutrophils to lymphocytes ratio in patients with metastatic soft tissue sarcoma" 367: 261: 976: 920: 480: 282: 105: 499:

Multiple factors determine whether tumor cells will be eliminated by the immune system or will escape detection.

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Wullkopf L, West AK, Leijnse N, Cox TR, Madsen CD, Oddershede LB, et al. (October 2018). Discher D (ed.).

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within the tumor microenvironment. Reports emerged detailing the presence and activities of tumor-infiltrating

32: 2400:"How and Why Are Cancers Acidic? Carbonic Anhydrase IX and the Homeostatic Control of Tumour Extracellular pH" 770:

and other common genetic variants in modulating the tumor immune landscape and driving therapeutic outcomes.

5307:"Bevacizumab (Avastin®) in cancer treatment: A review of 15 years of clinical experience and future outlook" 445: 421: 328: 724: 4411:

Engblom C, Pfirschke C, Zilionis R, Da Silva Martins J, Bos SA, Courties G, et al. (December 2017).

2133: 4006:"Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells" 340: 1308:

Ghoshdastider U, Rohatgi N, Mojtabavi Naeini M, Baruah P, Revkov E, Guo YA, et al. (April 2021).

5081: 4589: 4532: 4473: 4367: 4308: 3687: 2878: 2575:"Extracellular Matrices and Cancer-Associated Fibroblasts: Targets for Cancer Diagnosis and Therapy?" 1845: 1143: 799: 728: 621: 396: 316: 65: 4576:

Finisguerra V, Di Conza G, Di Matteo M, Serneels J, Costa S, Thompson AA, et al. (June 2015).

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da Costa VR, Araldi RP, Vigerelli H, D'Ámelio F, Mendes TB, Gonzaga V, et al. (October 2021).

823:. However, as some important, normal tissues, such as the liver and kidneys, also have fenestrated 678:(IFN-γ). Th-1 cells supports the activation and proliferation of CD8+ cells by secreting IFN-γ and 651: 465: 461: 265: 187:

In later stages of tumor progression endothelial cells can differentiate into carcinoma associated

135: 115: 3046:"The Role of Extracellular Matrix Remodeling in Skin Tumor Progression and Therapeutic Resistance" 5528: 5097: 4921: 4712:

Whiteside TL (2022). "Tumor-Infiltrating Lymphocytes and Their Role in Solid Tumor Progression".

4228: 4179: 4087: 3986: 3942: 3849: 3721: 3660: 3257: 1744: 1505: 1408:"Advances in the role of gut microbiota in the regulation of the tumor microenvironment (Review)" 1388: 1339: 972: 898: 832: 589:, and are recruited to the tumor as a response to cancer-associated inflammation. Their sluggish 479:(CD44), DDR2 and elastin-binding protein receptor (EBPR) can activate signaling pathways such as 425: 352: 253: 245: 4154:

Engblom C, Pfirschke C, Pittet MJ (July 2016). "The role of myeloid cells in cancer therapies".

5115:

Raju GS, Pavitra E, Varaprasad GL, Bandaru SS, Nagaraju GP, Farran B, et al. (June 2022).

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Sahai E, Astsaturov I, Cukierman E, DeNardo DG, Egeblad M, Evans RM, et al. (March 2020).

2865:

Cords L, Tietscher S, Anzeneder T, Langwieder C, Rees M, de Souza N, et al. (2023-07-18).

2634:"Remodeling of Stromal Cells and Immune Landscape in Microenvironment During Tumor Progression" 5717: 5709: 5686:

Schubert ML, Schmitt M, Wang L, Ramos CA, Jordan K, Müller-Tidow C, et al. (2021-01-01).

5668: 5612: 5585: 5567: 5520: 5512: 5477: 5459: 5413: 5387: 5336: 5328: 5287: 5260: 5231:"Intelligent design of multifunctional lipid-coated nanoparticle platforms for cancer therapy" 5211: 5148: 4972: 4913: 4878: 4843: 4802: 4753: 4735: 4725: 4664: 4615: 4558: 4501: 4442: 4393: 4336: 4277: 4220: 4171: 4136: 4079: 4037: 3978: 3934: 3898: 3841: 3800: 3759: 3713: 3652: 3644: 3594: 3576: 3535: 3517: 3478: 3460: 3419: 3401: 3357: 3339: 3300: 3292: 3249: 3241: 3203: 3185: 3144: 3126: 3085: 3067: 3026: 3008: 2969: 2951: 2912: 2894: 2844: 2836: 2792: 2774: 2735: 2717: 2673: 2655: 2614: 2596: 2555: 2537: 2491: 2473: 2431: 2380: 2362: 2314: 2296: 2257: 2239: 2198: 2149: 2114: 2096: 2057: 2039: 2000: 1982: 1938: 1920: 1879: 1861: 1793: 1785: 1736: 1728: 1689: 1671: 1630: 1612: 1571: 1553: 1497: 1489: 1445: 1427: 1380: 1331: 1290: 1255: 1213: 1161: 1107: 1053: 1035: 887: 767: 671: 647: 602: 521: 416: 219: 153: 92:

established a connection between inflammation and cancer. However, it was not until 1889 that

5117:"Nanoparticles mediated tumor microenvironment modulation: current advances and applications" 3224:

Mohan V, Das A, Sagi I (2020-05-01). "Emerging roles of ECM remodeling processes in cancer".

2018:

Bhat SM, Badiger VA, Vasishta S, Chakraborty J, Prasad S, Ghosh S, et al. (2021-12-01).

1591:"Factors involved in cancer metastasis: a better understanding to "seed and soil" hypothesis" 1359:"Modelling the microenvironment of the most aggressive brain tumours for preclinical studies" 723:

models have been developed that seek to replicate the TME in a controlled environment. Tumor

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Coffelt SB, Kersten K, Doornebal CW, Weiden J, Vrijland K, Hau CS, et al. (June 2015).

4326: 4316: 4267: 4259: 4210: 4163: 4126: 4118: 4071: 4027: 4017: 3970: 3926: 3888: 3880: 3831: 3790: 3779:"Smoldering and polarized inflammation in the initiation and promotion of malignant disease" 3751: 3703: 3695: 3636: 3584: 3566: 3525: 3509: 3468: 3450: 3409: 3391: 3380:"The Extracellular Matrix: Its Composition, Function, Remodeling, and Role in Tumorigenesis" 3347: 3331: 3284: 3233: 3193: 3175: 3134: 3116: 3075: 3057: 3016: 3000: 2959: 2943: 2902: 2886: 2828: 2782: 2766: 2725: 2707: 2663: 2645: 2604: 2586: 2545: 2529: 2481: 2465: 2421: 2411: 2370: 2352: 2304: 2288: 2247: 2229: 2190: 2141: 2104: 2088: 2047: 2031: 1990: 1974: 1928: 1910: 1869: 1853: 1775: 1720: 1679: 1661: 1620: 1602: 1561: 1545: 1481: 1435: 1419: 1370: 1321: 1282: 1247: 1203: 1195: 1151: 1097: 1087: 1043: 1025: 914: 828: 779: 675: 663: 249: 211: 73: 53: 5305:

Garcia J, Hurwitz HI, Sandler AB, Miles D, Coleman RL, Deurloo R, et al. (June 2020).

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Pagadala M, Sears TJ, Wu VH, Pérez-Guijarro E, Kim H, Castro A, et al. (12 May 2023).

4297:"Circulating hematopoietic stem and progenitor cells are myeloid-biased in cancer patients" 508: 17: 5548:"CAR T cell therapy and the tumor microenvironment: Current challenges and opportunities" 5412:, Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases, 2012, 4356:"IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis" 4197:

Huang SH, Waldron JN, Milosevic M, Shen X, Ringash J, Su J, et al. (February 2015).

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Tumor-associated immune cells in the tumor microenvironment (TME) of breast cancer models

534:

Tumor-associated immune cells in the tumor microenvironment (TME) of breast cancer models

5085: 5057: 5032: 4593: 4536: 4477: 4371: 4312: 3691: 3678:

Mantovani A, Allavena P, Sica A, Balkwill F (July 2008). "Cancer-related inflammation".

3414: 3379: 2907: 2882: 2867:"Cancer-associated fibroblast classification in single-cell and spatial proteomics data" 2866: 2787: 2754: 2550: 2517: 2109: 2076: 1849: 1440: 1407: 1147: 810:

suppresses tumor growth by inducing transition of macrophages to proinflammatory types.

76:, while the immune cells in the microenvironment can affect the growth and evolution of 5741: 5663: 5636: 5580: 5547: 5472: 5437: 5382: 5355: 5255: 5230: 5143: 5116: 5016: 4991: 4967: 4940: 4797: 4772: 4748: 4659: 4634: 4610: 4577: 4553: 4520: 4496: 4461: 4460:

Casbon AJ, Reynaud D, Park C, Khuc E, Gan DD, Schepers K, et al. (February 2015).

4437: 4412: 4388: 4355: 4331: 4296: 4272: 4247: 4131: 4106: 4032: 4005: 3893: 3868: 3818:

Biswas SK, Gangi L, Paul S, Schioppa T, Saccani A, Sironi M, et al. (March 2006).

3589: 3554: 3530: 3497: 3473: 3438: 3352: 3319: 3198: 3163: 3139: 3104: 3080: 3045: 3021: 2988: 2964: 2931: 2730: 2695: 2668: 2633: 2609: 2574: 2486: 2426: 2399: 2375: 2340: 2309: 2252: 2217: 2145: 2052: 2019: 1995: 1962: 1933: 1898: 1874: 1833: 1684: 1649: 1625: 1590: 1566: 1533: 1208: 1183: 1102: 1075: 1048: 1013: 495: 89: 61: 5180: 4107:"The prognostic landscape of genes and infiltrating immune cells across human cancers" 3164:"Tumor Microenvironment: Extracellular Matrix Alterations Influence Tumor Progression" 5735: 5532: 5101: 4105:

Gentles AJ, Newman AM, Liu CL, Bratman SV, Feng W, Kim D, et al. (August 2015).

3664: 3261: 3162:

Brassart-Pasco S, Brézillon S, Brassart B, Ramont L, Oudart JB, Monboisse JC (2020).

2816: 1392: 1343: 955: 787: 732: 679: 667: 363: 231: 93: 5635:

Brown CE, Aguilar B, Starr R, Yang X, Chang WC, Weng L, et al. (January 2018).

4925: 4521:"Neutrophils support lung colonization of metastasis-initiating breast cancer cells" 4183: 3990: 3946: 3237: 1748: 1708: 1509: 786:

and reducing the likelihood of cancer occurrence. Strategies included regulation of

315:. These cells can originate from neighboring non-cancerous stromal cells or undergo 5278:

Jain RK (June 1987). "Transport of molecules in the tumor interstitium: a review".

4941:"3D Cancer Models: Depicting Cellular Crosstalk within the Tumour Microenvironment" 4861:

Clayton A, Tabi Z (May–June 2005). "Exosomes and the MICA-NKG2D system in cancer".

4413:"Osteoblasts remotely supply lung tumors with cancer-promoting SiglecF neutrophils" 4091: 3853: 3725: 1406:

Xinyuan T, Lei Y, Jianping S, Rongwei Z, Ruiwen S, Ye Z, et al. (2023-10-01).

968: 864: 791: 586: 571: 469: 412: 400: 356: 312: 294: 181: 157: 139: 110: 69: 49: 5546:

Kankeu Fonkoua LA, Sirpilla O, Sakemura R, Siegler EL, Kenderian SS (2022-06-16).

4838: 4821: 4232: 2194: 2134:"Chapter 13 - Therapeutic Nanoparticles for Targeted Delivery of Anticancer Drugs" 1470:"Paget's "Seed and Soil" Theory of Cancer Metastasis: An Idea Whose Time has Come" 1326: 1309: 971:

suggested improved anti-tumor activity and engineering these cells to overexpress

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There are several types of T cells that are important to tumorigenesis, including

347:(ETM), or endothelial cells trough endothelial to mesenchymal transition (EndMT). 5704: 5687: 5508: 4992:"STAT3-enhancing germline mutations contribute to tumor-extrinsic immune evasion" 3930: 3640: 3335: 2469: 1485: 1375: 1358: 1310:"Pan-Cancer Analysis of Ligand-Receptor Cross-talk in the Tumor Microenvironment" 1251: 1199: 913:

are common in cancer cells, making them attractive targets for anticancer drugs.

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and are much better at recreating the tumour architecture than 2D cell cultures.

5653: 4721: 4056: 3755: 2696:"Cancer-Associated Fibroblasts: Tumorigenicity and Targeting for Cancer Therapy" 2518:"Stromal cells in the tumor microenvironment: accomplices of tumor progression?" 2092: 1780: 1763: 848: 824: 811: 807: 617: 585:

Tumor-associated macrophages are a central component in the strong link between

404: 305: 278: 173: 5604: 5563: 5405: 5372: 5323: 5306: 5133: 5048: 4874: 4820:

Valenti R, Huber V, Iero M, Filipazzi P, Parmiani G, Rivoltini L (April 2007).

4788: 4466:

Proceedings of the National Academy of Sciences of the United States of America

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Proceedings of the National Academy of Sciences of the United States of America

3884: 3836: 3819: 3396: 3121: 2890: 2832: 2817:"Cancer-associated fibroblasts: overview, progress, challenges, and directions" 2770: 2533: 2035: 1915: 1650:"Exosomes in the Tumor Microenvironment: From Biology to Clinical Applications" 1286: 1014:"Hepatic Tumor Microenvironments and Effects on NK Cell Phenotype and Function" 566:

origin that are considered tumor promoting. They have the potential to repress

5454: 5093: 4650: 3974: 3795: 3778: 3288: 3062: 2947: 2932:"A framework for advancing our understanding of cancer-associated fibroblasts" 2815:

Ping Q, Yan R, Cheng X, Wang W, Zhong Y, Hou Z, et al. (September 2021).

2234: 1978: 1857: 1724: 1607: 1549: 951: 883: 874:

Targeting immunoregulatory membrane receptors succeeded in some patients with

783: 695: 687: 579: 371: 301: 274: 257: 192: 188: 123: 97: 57: 5713: 5571: 5516: 5463: 5332: 4739: 4263: 4022: 3648: 3580: 3521: 3464: 3405: 3343: 3296: 3245: 3189: 3130: 3071: 3012: 2955: 2898: 2840: 2778: 2721: 2659: 2650: 2600: 2541: 2477: 2366: 2357: 2300: 2243: 2100: 2043: 1986: 1924: 1897:

Jiang X, Wang J, Deng X, Xiong F, Zhang S, Gong Z, et al. (2020-09-30).

1865: 1789: 1732: 1675: 1616: 1557: 1493: 1431: 1384: 1184:"Impact of the physical microenvironment on tumor progression and metastasis" 1039: 550:

Immune checkpoints of immunosuppressive actions associated with breast cancer

4957: 4633:

Granot Z, Henke E, Comen EA, King TA, Norton L, Benezra R (September 2011).

4486: 4428: 4321: 3571: 3513: 3180: 2712: 2591: 2416: 2077:"Cancer hallmarks intersect with neuroscience in the tumor microenvironment" 1156: 1131: 980: 932: 928: 924: 851:

is clinically approved in the US to treat a variety of cancers by targeting

820: 691: 504: 464:, survival, migration, and invasion in response to ECM changes. They act as 215: 5721: 5672: 5616: 5589: 5524: 5481: 5417: 5391: 5340: 5264: 5215: 5152: 4976: 4917: 4882: 4847: 4806: 4757: 4668: 4619: 4562: 4505: 4446: 4397: 4340: 4281: 4224: 4175: 4140: 4083: 4041: 3982: 3938: 3902: 3845: 3804: 3763: 3717: 3656: 3598: 3539: 3482: 3423: 3361: 3304: 3253: 3207: 3148: 3089: 3030: 2973: 2916: 2848: 2796: 2739: 2677: 2618: 2559: 2495: 2435: 2384: 2318: 2276: 2261: 2202: 2118: 2061: 2004: 1942: 1883: 1797: 1740: 1693: 1634: 1575: 1501: 1449: 1335: 1294: 1259: 1217: 1165: 1111: 1092: 1057: 979:(CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and 160:

is upregulated to feed the cancer cells and is linked to tumor malignancy.

138:. Researchers observed that tumor-infiltrating T cells had both anti-tumor 5688:"Side-effect management of chimeric antigen receptor (CAR) T-cell therapy" 5291: 1666: 180:(VEGF). VEGF activates the endothelial cells, which begins the process of 4246:

Jiang L, Jiang S, Situ D, Lin Y, Yang H, Li Y, et al. (April 2015).

3455: 2755:"Cancer-associated fibroblasts: from basic science to anticancer therapy" 2138:

Multifunctional Systems for Combined Delivery, Biosensing and Diagnostics

1423: 1030: 875: 754: 736: 606: 590: 457: 449: 433: 429: 408: 45: 5410:

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury

4601: 4544: 4379: 4295:

Wu WC, Sun HW, Chen HT, Liang J, Yu XJ, Wu C, et al. (March 2014).

4167: 4075: 3699: 2277:"Hypoxia-inducible factors: cancer progression and clinical translation" 88:

The concept of the tumor microenvironment (TME) dates back to 1863 when

5246: 4909: 4635:"Tumor entrained neutrophils inhibit seeding in the premetastatic lung" 4215: 4198: 4004:

Yang M, Chen J, Su F, Yu B, Su F, Lin L, et al. (September 2011).

3708: 3105:"The Role of the Extracellular Matrix (ECM) in Wound Healing: A Review" 2516:

Zhao Y, Shen M, Wu L, Yang H, Yao Y, Yang Q, et al. (2023-09-04).

816: 741: 620:

are polymorphonuclear immune cells that are critical components of the

582:

with the M2 phenotype are considered myeloid-derived suppressor cells.

563: 122:

In the late 1970s, attention shifted towards understanding the role of

5207: 2292: 1764:"Tumor angiogenesis: Current challenges and therapeutic opportunities" 5007: 1069: 1067: 959: 910: 891: 567: 131: 127: 77: 4990:

Kogan D, Grabner A, Yanucil C, Faul C, Ulaganathan VK (1 May 2018).

4122: 3004: 2341:"Role of hypoxia in the tumor microenvironment and targeted therapy" 1132:"T cell exclusion, immune privilege, and the tumor microenvironment" 407:. In healthy skin, the EMC is composed of various molecules such as 4939:

Franchi-Mendes T, Eduardo R, Domenici G, Brito C (September 2021).

359:. CAFs may also exhibit tumor-inhibitory properties in some cases. 4578:"MET is required for the recruitment of anti-tumoural neutrophils" 895: 545: 537: 529: 420:

in protein content and enzymatic activity which influences signal

386: 235: 31: 2989:"Remodelling the extracellular matrix in development and disease" 2573:

Belhabib I, Zaghdoudi S, Lac C, Bousquet C, Jean C (2021-07-11).

1238:

Weber CE, Kuo PC (September 2012). "The tumor microenvironment".

962:

to effectively target tumor cells. CARs are programmed to target

555:

Myeloid-derived suppressor cells and tumor-associated macrophages

5438:"Targeting tumour microenvironment by tyrosine kinase inhibitor" 3869:"Macrophage diversity enhances tumor progression and metastasis" 3555:"The Functional Role of Extracellular Matrix Proteins in Cancer" 476: 4822:"Tumor-released microvesicles as vehicles of immunosuppression" 27:

Surroundings of tumors including nearby cells and blood vessels

2020:"3D tumor angiogenesis models: recent advances and challenges" 1012:

Piñeiro Fernández J, Luddy KA, Harmon C, O'Farrelly C (2019).

484: 5436:

Tan HY, Wang N, Lam W, Guo W, Feng Y, Cheng YC (2018-02-19).

5497:

The International Journal of Biochemistry & Cell Biology

4716:. Experientia Supplementum. Vol. 113. pp. 89–106. 1589:

Liu Q, Zhang H, Jiang X, Qian C, Liu Z, Luo D (2017-12-02).

1532:

Mao Y, Keller ET, Garfield DH, Shen K, Wang J (2013-06-01).

901:(Tregs) whose presence may impair effector T cell function. 831:

do not usually develop with the tumor, leading to increased

168:

In hypoxic environments the tissue sends out signals called

3320:"The Extracellular Matrix Modulates the Metastatic Journey" 1762:

Al-Ostoot FH, Salah S, Khamees HA, Khanum SA (2021-01-01).

1534:"Stromal cells in tumor microenvironment and breast cancer" 3437:

Giussani M, Triulzi T, Sozzi G, Tagliabue E (2019-01-23).

1468:

Akhtar M, Haider A, Rashid S, Al-Nabet AD (January 2019).

1177: 1175: 749:

Human germline genetic variants and tumor microenvironment

702:

replication, although this also occurs within the tumor.

609:

into cancerous cells, specifically breast cancer cells.

1182:

Spill F, Reynolds DS, Kamm RD, Zaman MH (August 2016).

601:

Tumor-associated macrophages are associated with using

4055:

Coffelt SB, Wellenstein MD, de Visser KE (July 2016).

1903:

Journal of Experimental & Clinical Cancer Research

1074:

Alfarouk KO, Muddathir AK, Shayoub ME (January 2011).

48:, composed of cancer cells, stromal tissue (including 578:(VEGF), and can promote metastasis. Tumor associated 2216:

Tang M, Bolderson E, O'Byrne KJ, Richard DJ (2021).

1899:"The role of microenvironment in tumor angiogenesis" 475:

In addition to integrins, other cell receptors like

468:

by converting mechanical forces from the ECM or the

399:(ECM) is a tree-dimensional network of proteins and 277:. Cells with an elevated glucose metabolism produce 3777:Balkwill F, Charles KA, Mantovani A (March 2005). 332:Stromal cell types in early and late-stage tumors. 3279:. Cell-to-cell contact and extracellular matrix. 5354:Li C, Jiang P, Wei S, Xu X, Wang J (July 2020). 2024:Journal of Cancer Research and Clinical Oncology 444:Cells interact with and bind to the ECM through 240:Tumor stroma and extracellular matrix in hypoxia 5611:, Treasure Island (FL): StatPearls Publishing, 2694:Glabman RA, Choyke PL, Sato N (January 2022). 939:(EGFRs) in cancer by blocking the activity of 5603:Zhang C, Durer S, Thandra KC, Kasi A (2024), 2753:Yang D, Liu J, Qian H, Zhuang Q (July 2023). 1967:Technology in Cancer Research & Treatment 894:therapy leads to clearance from the tumor of 766:have highlighted the role of STAT3-enhancing 8: 4773:"Immunotherapy for metastatic solid cancers" 1768:Cancer Treatment and Research Communications 1125: 1123: 1121: 753:Recent research has demonstrated that human 2222:Frontiers in Cell and Developmental Biology 1018:International Journal of Molecular Sciences 782:have led to progress in suppressing cancer 562:are a heterogeneous population of cells of 5605:"Chimeric Antigen Receptor T-Cell Therapy" 3737: 3735: 2218:"Tumor Hypoxia Drives Genomic Instability" 2176: 2174: 2172: 2170: 1709:"A history of exploring cancer in context" 205:Enhanced permeability and retention effect 199:Enhanced permeability and retention effect 5703: 5662: 5652: 5579: 5471: 5453: 5381: 5371: 5322: 5254: 5142: 5132: 5056: 5015: 4966: 4956: 4837: 4796: 4747: 4658: 4609: 4552: 4495: 4485: 4436: 4387: 4330: 4320: 4271: 4214: 4130: 4031: 4021: 3892: 3835: 3794: 3707: 3588: 3570: 3529: 3472: 3454: 3413: 3395: 3351: 3318:Kai F, Drain AP, Weaver VM (2019-05-06). 3197: 3179: 3138: 3120: 3079: 3061: 3020: 2963: 2906: 2786: 2729: 2711: 2667: 2649: 2608: 2590: 2549: 2485: 2454:"The Role of Stroma in Tumor Development" 2425: 2415: 2374: 2356: 2308: 2251: 2233: 2108: 2051: 1994: 1932: 1914: 1873: 1779: 1683: 1665: 1624: 1606: 1565: 1439: 1374: 1325: 1207: 1155: 1101: 1091: 1047: 1029: 958:treatment that uses genetically modified 871:, but its uses now span various cancers. 739:are generally derived from stem cells or 5196:Journal of the American Chemical Society 4057:"Neutrophils in cancer: neutral no more" 2987:Bonnans C, Chou J, Werb Z (2015-02-04). 2339:Chen G, Wu K, Li H, Xia D, He T (2022). 1963:"Hypoxia and the Tumor Microenvironment" 835:pressure, which may block tumor access. 494: 327: 5229:Ramishetti S, Huang L (December 2012). 4519:Wculek SK, Malanchi I (December 2015). 1363:Advances in Cancer Biology - Metastasis 1233: 1231: 1229: 1227: 1004: 983:, becomes increasingly more important. 952:Chimeric antigen receptors (CAR) T cell 5169:International Journal of Pharmaceutics 4714:Interaction of Immune and Cancer Cells 3373: 3371: 3219: 3217: 2860: 2858: 2810: 2808: 2806: 2689: 2687: 1827: 947:Chimeric antigen receptor cell therapy 4863:Blood Cells, Molecules & Diseases 4707: 4705: 4703: 3622: 3620: 3618: 3616: 3614: 3612: 3610: 3608: 2993:Nature Reviews Molecular Cell Biology 2759:Experimental & Molecular Medicine 2511: 2509: 2507: 2505: 2447: 2445: 2334: 2332: 2330: 2328: 2281:The Journal of Clinical Investigation 1956: 1954: 1952: 1832:Anderson NM, Simon MC (August 2020). 1825: 1823: 1821: 1819: 1817: 1815: 1813: 1811: 1809: 1807: 1527: 1525: 1523: 1521: 1519: 1463: 1461: 1459: 1076:"Tumor acidity as evolutionary spite" 375:affects the behavior of tumor cells. 44:is a complex ecosystem surrounding a 7: 3553:Popova NV, Jücker M (January 2022). 3228:. Translating Extracellular Matrix. 436:secreted by tumor or stromal cells. 256:by downregulating genes involved in 2275:Wicks EE, Semenza GL (2022-06-01). 690:. Another is the expression of the 248:in the tumor microenvironment, the 3867:Qian BZ, Pollard JW (April 2010). 3103:Diller RB, Tabor AJ (2022-07-01). 3050:Frontiers in Molecular Biosciences 2398:Lee SH, Griffiths JR (June 2020). 2146:10.1016/b978-0-323-52725-5.00013-7 1961:Li Y, Zhao L, Li XF (2021-08-05). 1130:Joyce JA, Fearon DT (April 2015). 993:Tumor-associated endothelial cells 596:vascular endothelial growth factor 576:vascular endothelial growth factor 477:cell surface glycoprotein receptor 244:While angiogenesis can reduce the 178:vascular endothelial growth factor 164:Endothelial cells and angiogenesis 25: 4996:Journal of Clinical Investigation 4771:Turcotte S, Rosenberg SA (2011). 3378:Dzobo K, Dandara C (2023-04-05). 2452:Werb Z, Lu P (July–August 2015). 2075:Hanahan D, Monje M (2023-03-13). 937:epidermal growth factor receptors 760:Journal of Clinical Investigation 605:to deliver invasion-potentiating 345:epithelial-mesenchymal transition 176: to secrete factors such as 172:(HIFs) that can stimulate nearby 1188:Current Opinion in Biotechnology 867:. It was initially approved for 857:carcinoma associated fibroblasts 560:Myeloid-derived suppressor cells 343:(MSCs), cancer cells undergoing 337:Carcinoma-associated fibroblasts 324:Carcinoma-associated fibroblasts 308:, and various other cell types. 4683:"tumor-infiltrating lymphocyte" 3277:Current Opinion in Cell Biology 3238:10.1016/j.semcancer.2019.09.004 587:chronic inflammation and cancer 383:Extracellular matrix remodeling 5552:Molecular Therapy - Oncolytics 2140:, Elsevier, pp. 245–259, 1707:Maman S, Witz IP (June 2018). 1474:Advances in Anatomic Pathology 638:Tumor-infiltrating lymphocytes 632:Tumor infiltrating lymphocytes 574:by producing proteins such as 1: 5181:10.1016/S0378-5173(96)04674-1 4839:10.1158/0008-5472.CAN-07-0520 3502:Molecular Biology of the Cell 3044:Fromme JE, Zigrino P (2022). 2195:10.1016/j.jconrel.2010.08.027 2183:Journal of Controlled Release 1538:Cancer and Metastasis Reviews 1327:10.1158/0008-5472.CAN-20-2352 880:non-small-cell lung carcinoma 796:cancer-associated fibroblasts 481:phosphatidylinositol 3-kinase 5705:10.1016/j.annonc.2020.10.478 5509:10.1016/j.biocel.2021.106087 5121:Journal of Nanobiotechnology 5074:Chemical Engineering Journal 3931:10.3109/10428194.2010.529204 3641:10.1016/j.canlet.2019.11.009 3336:10.1016/j.devcel.2019.03.026 2470:10.1097/PPO.0000000000000127 1834:"The tumor microenvironment" 1486:10.1097/PAP.0000000000000219 1376:10.1016/j.adcanc.2021.100017 1252:10.1016/j.suronc.2011.09.001 1200:10.1016/j.copbio.2016.02.007 869:metastatic colorectal cancer 861:tumor-associated macrophages 855:, which is produced by both 804:tumor-associated macrophages 491:Impact on cancer progression 5654:10.1016/j.ymthe.2017.10.002 5406:"Protein Kinase Inhibitors" 4722:10.1007/978-3-030-91311-3_3 3756:10.1016/j.jprot.2012.10.016 2093:10.1016/j.ccell.2023.02.012 1781:10.1016/j.ctarc.2021.100422 1357:Žavbi J, Breznik B (2021). 778:Advancements in remodeling 454:discoidin domain receptor 2 74:peripheral immune tolerance 5758: 5564:10.1016/j.omto.2022.03.009 5373:10.1186/s12943-020-01234-1 5324:10.1016/j.ctrv.2020.102017 5134:10.1186/s12951-022-01476-9 5049:10.1038/s41467-023-38271-5 4875:10.1016/j.bcmd.2005.03.003 4789:10.1016/j.yasu.2011.04.003 3885:10.1016/j.cell.2010.03.014 3837:10.1182/blood-2005-01-0428 3397:10.3390/biomimetics8020146 3226:Seminars in Cancer Biology 3122:10.3390/biomimetics7030087 2891:10.1038/s41467-023-39762-1 2833:10.1038/s41417-021-00318-4 2771:10.1038/s12276-023-01013-0 2534:10.1038/s41419-023-06110-6 2036:10.1007/s00432-021-03814-0 1916:10.1186/s13046-020-01709-5 1287:10.1016/j.cyto.2016.01.021 921:Tyrosine kinase inhibitors 635: 519: 391:HIF regulates cancer cells 368:single-cell RNA sequencing 292: 262:nucleotide excision repair 229: 202: 18:Microenvironment (biology) 5455:10.1186/s12943-018-0800-6 5094:10.1016/j.cej.2022.139506 4651:10.1016/j.ccr.2011.08.012 3975:10.1007/s12032-010-9638-5 3796:10.1016/j.ccr.2005.02.013 3289:10.1016/j.ceb.2006.08.009 3063:10.3389/fmolb.2022.864302 2948:10.1038/s41568-019-0238-1 2235:10.3389/fcell.2021.626229 1979:10.1177/15330338211036304 1858:10.1016/j.cub.2020.06.081 1725:10.1038/s41568-018-0006-7 1608:10.1186/s12943-017-0742-4 1550:10.1007/s10555-012-9415-3 977:cytokine release syndrome 964:tumor-associated antigens 432:, inflammatory cells, or 362:CAFs play a dual role in 170:hypoxia inducible factors 136:natural killer (NK) cells 5311:Cancer Treatment Reviews 4264:10.18632/oncotarget.3283 4023:10.1186/1476-4598-10-117 2651:10.3389/fonc.2021.596798 2522:Cell Death & Disease 2358:10.3389/fonc.2022.961637 941:protein tyrosine kinases 4958:10.3390/cancers13184610 4487:10.1073/pnas.1424927112 4429:10.1126/science.aal5081 4322:10.1073/pnas.1320753111 3919:Leukemia & Lymphoma 3572:10.3390/cancers14010238 3514:10.1091/mbc.E18-05-0319 3181:10.3389/fonc.2020.00397 2713:10.3390/cancers14163906 2632:Arora L, Pal D (2021). 2592:10.3390/cancers13143466 2417:10.3390/cancers12061616 1157:10.1126/science.aaa6204 725:immortalised cell lines 570:responses, can support 446:transmembrane receptors 4156:Nature Reviews. Cancer 4064:Nature Reviews. Cancer 1093:10.3390/cancers3010408 551: 543: 535: 500: 392: 341:mesenchymal stem cells 333: 241: 42:tumor microenvironment 37: 5037:Nature Communications 3744:Journal of Proteomics 3168:Frontiers in Oncology 2936:Nature Reviews Cancer 2871:Nature Communications 2638:Frontiers in Oncology 2345:Frontiers in Oncology 1973:: 15330338211036304. 1713:Nature Reviews Cancer 1667:10.3390/cells10102617 764:Nature Communications 729:primary cell cultures 549: 541: 533: 498: 390: 331: 239: 35: 5235:Therapeutic Delivery 3456:10.3390/cells8020081 1424:10.3892/or.2023.8618 1031:10.3390/ijms20174131 800:extracellular matrix 652:natural killer cells 622:innate immune system 397:extracellular matrix 317:transdifferentiation 66:extracellular matrix 5202:(32): 13152–13155. 5086:2023ChEnJ.45239506F 4777:Advances in Surgery 4602:10.1038/nature14407 4594:2015Natur.522..349F 4545:10.1038/nature16140 4537:2015Natur.528..413W 4478:2015PNAS..112E.566C 4380:10.1038/nature14282 4372:2015Natur.522..345C 4313:2014PNAS..111.4221W 4168:10.1038/nrc.2016.54 4076:10.1038/nrc.2016.52 3700:10.1038/nature07205 3692:2008Natur.454..436M 2883:2023NatCo..14.4294C 2821:Cancer Gene Therapy 1850:2020CBio...30.R921A 1148:2015Sci...348...74J 973:chemokine receptors 886:bladder cancer and 440:Cellular mechanisms 260:mechanisms such as 254:genetic instability 62:signaling molecules 5692:Annals of Oncology 5247:10.4155/tde.12.127 4910:10.1038/nmeth.3403 4423:(6367): eaal5081. 4216:10.1002/cncr.29100 3324:Developmental Cell 2458:The Cancer Journal 899:regulatory T cells 833:interstitial fluid 768:germline mutations 672:regulatory T cells 552: 544: 536: 501: 466:mechanotransducers 417:glycosaminoglycans 393: 353:cell-cell adhesion 334: 242: 70:tumor angiogenesis 38: 5641:Molecular Therapy 5286:(12): 3039–3051. 5241:(12): 1429–1445. 5208:10.1021/ja302743g 4731:978-3-030-91310-6 4588:(7556): 349–353. 4531:(7582): 413–417. 4366:(7556): 345–348. 4307:(11): 4221–4226. 4258:(11): 9542–9550. 3686:(7203): 436–444. 3508:(20): 2378–2385. 2293:10.1172/JCI159839 2155:978-0-323-52725-5 2030:(12): 3477–3494. 1844:(16): R921–R925. 1240:Surgical Oncology 915:Kinase inhibitors 905:Kinase inhibitors 888:renal cell cancer 829:Lymphatic vessels 670:(Th-1) cells and 664:cytotoxic T cells 522:Cancer immunology 306:endothelial cells 220:basement membrane 191:, which furthers 174:endothelial cells 154:passive diffusion 16:(Redirected from 5749: 5726: 5725: 5707: 5683: 5677: 5676: 5666: 5656: 5632: 5626: 5625: 5624: 5623: 5600: 5594: 5593: 5583: 5543: 5537: 5536: 5492: 5486: 5485: 5475: 5457: 5442:Molecular Cancer 5433: 5427: 5426: 5425: 5424: 5402: 5396: 5395: 5385: 5375: 5360:Molecular Cancer 5351: 5345: 5344: 5326: 5302: 5296: 5295: 5275: 5269: 5268: 5258: 5226: 5220: 5219: 5191: 5185: 5184: 5163: 5157: 5156: 5146: 5136: 5112: 5106: 5105: 5069: 5063: 5062: 5060: 5028: 5022: 5021: 5019: 5008:10.1172/JCI96708 5002:(5): 1867–1872. 4987: 4981: 4980: 4970: 4960: 4936: 4930: 4929: 4893: 4887: 4886: 4858: 4852: 4851: 4841: 4832:(7): 2912–2915. 4817: 4811: 4810: 4800: 4768: 4762: 4761: 4751: 4709: 4698: 4697: 4695: 4694: 4679: 4673: 4672: 4662: 4630: 4624: 4623: 4613: 4573: 4567: 4566: 4556: 4516: 4510: 4509: 4499: 4489: 4472:(6): E566–E575. 4457: 4451: 4450: 4440: 4408: 4402: 4401: 4391: 4351: 4345: 4344: 4334: 4324: 4292: 4286: 4285: 4275: 4243: 4237: 4236: 4218: 4194: 4188: 4187: 4151: 4145: 4144: 4134: 4102: 4096: 4095: 4061: 4052: 4046: 4045: 4035: 4025: 4010:Molecular Cancer 4001: 3995: 3994: 3969:(4): 1447–1452. 3963:Medical Oncology 3957: 3951: 3950: 3913: 3907: 3906: 3896: 3864: 3858: 3857: 3839: 3830:(5): 2112–2122. 3815: 3809: 3808: 3798: 3774: 3768: 3767: 3739: 3730: 3729: 3711: 3675: 3669: 3668: 3624: 3603: 3602: 3592: 3574: 3550: 3544: 3543: 3533: 3493: 3487: 3486: 3476: 3458: 3434: 3428: 3427: 3417: 3399: 3375: 3366: 3365: 3355: 3315: 3309: 3308: 3272: 3266: 3265: 3221: 3212: 3211: 3201: 3183: 3159: 3153: 3152: 3142: 3124: 3100: 3094: 3093: 3083: 3065: 3041: 3035: 3034: 3024: 2984: 2978: 2977: 2967: 2927: 2921: 2920: 2910: 2862: 2853: 2852: 2812: 2801: 2800: 2790: 2765:(7): 1322–1332. 2750: 2744: 2743: 2733: 2715: 2691: 2682: 2681: 2671: 2653: 2629: 2623: 2622: 2612: 2594: 2570: 2564: 2563: 2553: 2513: 2500: 2499: 2489: 2449: 2440: 2439: 2429: 2419: 2395: 2389: 2388: 2378: 2360: 2336: 2323: 2322: 2312: 2272: 2266: 2265: 2255: 2237: 2213: 2207: 2206: 2178: 2165: 2164: 2163: 2162: 2129: 2123: 2122: 2112: 2072: 2066: 2065: 2055: 2015: 2009: 2008: 1998: 1958: 1947: 1946: 1936: 1918: 1894: 1888: 1887: 1877: 1829: 1802: 1801: 1783: 1759: 1753: 1752: 1704: 1698: 1697: 1687: 1669: 1645: 1639: 1638: 1628: 1610: 1595:Molecular Cancer 1586: 1580: 1579: 1569: 1529: 1514: 1513: 1465: 1454: 1453: 1443: 1412:Oncology Reports 1403: 1397: 1396: 1378: 1354: 1348: 1347: 1329: 1320:(7): 1802–1812. 1305: 1299: 1298: 1270: 1264: 1263: 1235: 1222: 1221: 1211: 1179: 1170: 1169: 1159: 1127: 1116: 1115: 1105: 1095: 1071: 1062: 1061: 1051: 1033: 1009: 923:(TKIs), such as 890:. In mice, anti- 780:nanotherapeutics 774:Drug development 676:interferon-gamma 304:, immune cells, 250:partial pressure 218:and a malformed 212:lymphatic system 21: 5757: 5756: 5752: 5751: 5750: 5748: 5747: 5746: 5732: 5731: 5730: 5729: 5685: 5684: 5680: 5634: 5633: 5629: 5621: 5619: 5602: 5601: 5597: 5545: 5544: 5540: 5494: 5493: 5489: 5435: 5434: 5430: 5422: 5420: 5404: 5403: 5399: 5353: 5352: 5348: 5304: 5303: 5299: 5280:Cancer Research 5277: 5276: 5272: 5228: 5227: 5223: 5193: 5192: 5188: 5165: 5164: 5160: 5114: 5113: 5109: 5071: 5070: 5066: 5030: 5029: 5025: 4989: 4988: 4984: 4938: 4937: 4933: 4895: 4894: 4890: 4860: 4859: 4855: 4826:Cancer Research 4819: 4818: 4814: 4770: 4769: 4765: 4732: 4711: 4710: 4701: 4692: 4690: 4681: 4680: 4676: 4632: 4631: 4627: 4575: 4574: 4570: 4518: 4517: 4513: 4459: 4458: 4454: 4410: 4409: 4405: 4353: 4352: 4348: 4294: 4293: 4289: 4245: 4244: 4240: 4196: 4195: 4191: 4153: 4152: 4148: 4123:10.1038/nm.3909 4111:Nature Medicine 4104: 4103: 4099: 4059: 4054: 4053: 4049: 4003: 4002: 3998: 3959: 3958: 3954: 3915: 3914: 3910: 3866: 3865: 3861: 3817: 3816: 3812: 3776: 3775: 3771: 3741: 3740: 3733: 3677: 3676: 3672: 3626: 3625: 3606: 3552: 3551: 3547: 3495: 3494: 3490: 3436: 3435: 3431: 3377: 3376: 3369: 3317: 3316: 3312: 3274: 3273: 3269: 3223: 3222: 3215: 3161: 3160: 3156: 3102: 3101: 3097: 3043: 3042: 3038: 3005:10.1038/nrm3904 2999:(12): 786–801. 2986: 2985: 2981: 2929: 2928: 2924: 2864: 2863: 2856: 2814: 2813: 2804: 2752: 2751: 2747: 2693: 2692: 2685: 2631: 2630: 2626: 2572: 2571: 2567: 2515: 2514: 2503: 2451: 2450: 2443: 2397: 2396: 2392: 2338: 2337: 2326: 2274: 2273: 2269: 2215: 2214: 2210: 2180: 2179: 2168: 2160: 2158: 2156: 2131: 2130: 2126: 2074: 2073: 2069: 2017: 2016: 2012: 1960: 1959: 1950: 1896: 1895: 1891: 1838:Current Biology 1831: 1830: 1805: 1761: 1760: 1756: 1706: 1705: 1701: 1647: 1646: 1642: 1588: 1587: 1583: 1531: 1530: 1517: 1467: 1466: 1457: 1405: 1404: 1400: 1356: 1355: 1351: 1314:Cancer Research 1307: 1306: 1302: 1272: 1271: 1267: 1237: 1236: 1225: 1181: 1180: 1173: 1142:(6230): 74–80. 1129: 1128: 1119: 1073: 1072: 1065: 1011: 1010: 1006: 1001: 989: 967:CAR T cells in 949: 907: 863:, thus slowing 846: 841: 776: 751: 713: 708: 660: 640: 634: 615: 557: 524: 518: 509:type 1 collagen 493: 442: 385: 326: 297: 291: 266:mismatch repair 234: 228: 207: 201: 166: 149: 86: 28: 23: 22: 15: 12: 11: 5: 5755: 5753: 5745: 5744: 5734: 5733: 5728: 5727: 5678: 5627: 5595: 5538: 5487: 5428: 5397: 5346: 5297: 5270: 5221: 5186: 5158: 5107: 5064: 5023: 4982: 4931: 4904:(6): 493–497. 4898:Nature Methods 4888: 4869:(3): 206–213. 4853: 4812: 4763: 4730: 4699: 4687:www.cancer.gov 4674: 4645:(3): 300–314. 4625: 4568: 4511: 4452: 4403: 4346: 4287: 4238: 4209:(4): 545–555. 4189: 4162:(7): 447–462. 4146: 4117:(8): 938–945. 4097: 4070:(7): 431–446. 4047: 3996: 3952: 3908: 3859: 3810: 3789:(3): 211–217. 3769: 3731: 3670: 3629:Cancer Letters 3604: 3545: 3488: 3429: 3367: 3330:(3): 332–346. 3310: 3283:(5): 463–471. 3267: 3213: 3154: 3095: 3036: 2979: 2942:(3): 174–186. 2922: 2854: 2827:(9): 984–999. 2802: 2745: 2683: 2624: 2565: 2501: 2464:(4): 250–253. 2441: 2390: 2324: 2267: 2208: 2189:(2): 135–146. 2166: 2154: 2124: 2087:(3): 573–580. 2067: 2010: 1948: 1889: 1803: 1754: 1719:(6): 359–376. 1699: 1640: 1581: 1544:(1): 303–315. 1515: 1455: 1398: 1349: 1300: 1265: 1246:(3): 172–177. 1223: 1171: 1117: 1086:(1): 408–414. 1063: 1003: 1002: 1000: 997: 996: 995: 988: 985: 954:therapy is an 948: 945: 906: 903: 845: 842: 840: 837: 775: 772: 750: 747: 712: 709: 707: 704: 659: 656: 636:Main article: 633: 630: 614: 611: 556: 553: 520:Main article: 517: 514: 492: 489: 441: 438: 384: 381: 325: 322: 293:Main article: 290: 287: 283:Warburg effect 230:Main article: 227: 224: 203:Main article: 200: 197: 165: 162: 148: 145: 90:Rudolf Virchow 85: 82: 26: 24: 14: 13: 10: 9: 6: 4: 3: 2: 5754: 5743: 5740: 5739: 5737: 5723: 5719: 5715: 5711: 5706: 5701: 5697: 5693: 5689: 5682: 5679: 5674: 5670: 5665: 5660: 5655: 5650: 5646: 5642: 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1280: 1276: 1269: 1266: 1261: 1257: 1253: 1249: 1245: 1241: 1234: 1232: 1230: 1228: 1224: 1219: 1215: 1210: 1205: 1201: 1197: 1193: 1189: 1185: 1178: 1176: 1172: 1167: 1163: 1158: 1153: 1149: 1145: 1141: 1137: 1133: 1126: 1124: 1122: 1118: 1113: 1109: 1104: 1099: 1094: 1089: 1085: 1081: 1077: 1070: 1068: 1064: 1059: 1055: 1050: 1045: 1041: 1037: 1032: 1027: 1023: 1019: 1015: 1008: 1005: 998: 994: 991: 990: 986: 984: 982: 978: 974: 970: 965: 961: 960:T lymphocytes 957: 956:immunotherapy 953: 946: 944: 942: 938: 934: 930: 926: 922: 918: 916: 912: 904: 902: 900: 897: 893: 889: 885: 881: 877: 872: 870: 866: 862: 858: 854: 850: 843: 838: 836: 834: 830: 826: 822: 818: 813: 809: 805: 801: 797: 793: 789: 785: 781: 773: 771: 769: 765: 761: 756: 748: 746: 744: 743: 738: 734: 733:genetic drift 730: 726: 722: 718: 710: 705: 703: 699: 697: 693: 689: 683: 681: 680:interleukin-2 677: 673: 669: 665: 657: 655: 653: 649: 644: 639: 631: 629: 625: 623: 619: 612: 610: 608: 604: 599: 597: 592: 588: 583: 581: 577: 573: 569: 565: 561: 554: 548: 540: 532: 528: 523: 515: 513: 510: 506: 497: 490: 488: 486: 482: 478: 473: 471: 467: 463: 462:proliferation 459: 455: 451: 447: 439: 437: 435: 431: 427: 423: 418: 414: 413:glycoproteins 410: 406: 402: 401:proteoglycans 398: 389: 382: 380: 376: 373: 369: 365: 364:tumorigenesis 360: 358: 354: 348: 346: 342: 338: 330: 323: 321: 318: 314: 309: 307: 303: 296: 289:Stromal cells 288: 286: 284: 280: 276: 270: 267: 263: 259: 255: 251: 247: 238: 233: 232:Tumor hypoxia 225: 223: 221: 217: 213: 206: 198: 196: 194: 190: 185: 183: 179: 175: 171: 163: 161: 159: 155: 146: 144: 141: 137: 134:, as well as 133: 132:B lymphocytes 129: 125: 120: 117: 116:Isaiah Fidler 112: 107: 102: 99: 95: 94:Stephen Paget 91: 83: 81: 79: 75: 72:and inducing 71: 67: 63: 59: 55: 51: 50:blood vessels 47: 43: 34: 30: 19: 5698:(1): 34–48. 5695: 5691: 5681: 5647:(1): 31–44. 5644: 5640: 5630: 5620:, retrieved 5608: 5598: 5555: 5551: 5541: 5500: 5496: 5490: 5445: 5441: 5431: 5421:, retrieved 5409: 5400: 5363: 5359: 5349: 5314: 5310: 5300: 5283: 5279: 5273: 5238: 5234: 5224: 5199: 5195: 5189: 5175:(1): 11–17. 5172: 5168: 5161: 5124: 5120: 5110: 5077: 5073: 5067: 5040: 5036: 5026: 4999: 4995: 4985: 4951:(18): 4610. 4948: 4944: 4934: 4901: 4897: 4891: 4866: 4862: 4856: 4829: 4825: 4815: 4780: 4776: 4766: 4713: 4691:. 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