•Within the TME CAFs play an essential role in tumor progression.•CAFs are implicated in the induction of radioresistance.•Crosstalk between tumor cells, immune cells and CAFs dictates radiotherapy ...outcome.
Tumor growth is not only dictated by events involving tumor cells, but also by the environment they reside in, the so-called tumor microenvironment (TME). In the TME, cancer-associated fibroblasts (CAFs) are often the predominant cell type. CAFs were long considered to be of limited importance in the TME, but are now recognized for their pivotal role in cancer progression. Recently, it has become evident that different subsets of CAFs exist, with certain CAF subtypes having protumorigenic properties, whereas others show more antitumorigenic characteristics. Currently, the intricate interaction between the different subsets of CAFs with tumor cells, but also with immune cells that reside in the TME, is still poorly understood. This crosstalk of CAFs with tumor and immune cells in the TME largely dictates how a tumor responds to therapy and whether the tumor will eventually be eliminated, stay dormant or will progress and metastasize. Radiotherapy (RT) is a widely used and mostly very effective local cancer treatment, but CAFs are remarkably RT resistant. Although radiation does cause persistent DNA damage, CAFs do not die upon clinically applied doses of RT, but rather become senescent. Through the secretion of cytokines and growth factors they have been implicated in the induction of tumor radioresistance and recruitment of specific immune cells to the TME, thereby affecting local immune responses. In this review we will discuss the versatile role of CAFs in the TME and their influence on RT response.
Biology of Hypoxia Span, Paul N., PhD; Bussink, Johan, MD, PhD
Seminars in nuclear medicine,
03/2015, Letnik:
45, Številka:
2
Journal Article
Recenzirano
There is an important and strong, but complex influence of the tumor microenvironment on tumor cells׳ phenotype, aggressiveness, and treatment sensitivity. One of the most frequent and best-studied ...aspects of the tumor microenvironment is hypoxia. Low oxygen tension often occurs in tumor cells by several mechanisms, for example, poor angiogenesis and increased oxygen consumption. Hypoxia is a heterogeneous concept with oxygen tensions ranging from <0.01% (anoxia) to 5%, and can be chronic, acute, or cycling, all with differential effects on tumor cells. Quantification of tumor hypoxia can be performed directly or indirectly, and with exogenous or endogenous markers. Tumor cells launch different intracellular signaling pathways to survive hypoxia, such as hypoxia-inducible factor 1–mediated gene expression, the unfolded protein response, and AKT-mammalian target of rapamycin signaling. These pathways induce aggressive, metastatic, and treatment-insensitive tumors and are considered potential targets for (additive) therapy. Hypoxia leads to important, yet currently not well-understood changes in microRNA expression, epigenetics, and metabolism. Further, treatment-insensitive tumors arise through hypoxia-induced Darwinian selection of apoptosis-deficient, p53-mutated tumor cells. In conclusion, hypoxia has profound and largely still poorly understood effects on tumor cells with a major effect on the tumor׳s biology.
Cell-cell adhesion by adherens junctions controls proliferation and cell polarization and is crucial to maintain epithelial architecture and homeostasis. Downregulation of two of the main components ...of adherens junctions, E-cadherin and p120, is an often recurring hallmark of carcinomas, causing loss of polarity and increased proliferation, survival and invasion of epithelial cells. On the other hand, tumor-promoting effects of both E-cadherin and p120 have been reported, substantiated by sustained, or even elevated expression of these molecules in many cancers. In this review, we will discuss how expression regulation by EMT, E-cadherin cleavage or p120 isoform expression can contribute to either tumor-supressing or tumor-promoting processes. Furthermore, we will focus on the contradictory functions of E-cadherin and p120 in the different phases of tumor progression, from carcinoma in situ up to the formation of distant metastasis. Finally, we will discuss the possibilities and challenges when using either protein as a biomarker.
Radiotherapy, an important treatment modality in oncology, kills cells through induction of oxidative stress. However, malignant tumors vary in their response to irradiation as a consequence of ...resistance mechanisms taking place at the molecular level. It is important to understand these mechanisms of radioresistance, as counteracting them may improve the efficacy of radiotherapy. In this review, we describe how the hypoxia-inducible factor 1 (HIF-1) pathway has a profound effect on the response to radiotherapy. The main focus will be on HIF-1-controlled protection of the vasculature postirradiation and on HIF-1 regulation of glycolysis and the pentose phosphate pathway. This aberrant cellular metabolism increases the antioxidant capacity of tumors, thereby countering the oxidative stress caused by irradiation. From the results of translational studies and the first clinical phase I/II trials, it can be concluded that targeting HIF-1 and tumor glucose metabolism at several levels reduces the antioxidant capacity of tumors, affects the tumor microenvironment, and sensitizes various solid tumors to irradiation.
Abstract The tumour microenvironment contributes greatly to the response of tumour cells. It consists of chemical gradients, for example of oxygen and nutrients. However, a physical environment is ...also present. Apart from chemical input, cells also receive physical signals. Tumours display unique mechanical properties: they are a lot stiffer than normal tissue. This may be either a cause or a consequence of cancer, but literature suggests it has a major impact on tumour cells as will be described in this review. The mechanical microenvironment may cause malignant transformation, possibly through activation of oncogenic pathways and inhibition of tumour suppressor genes. In addition, the mechanical microenvironment may promote tumour progression by influencing processes such as epithelial-to-mesenchymal transition, enhancing cell survival through autophagy, but also affects sensitivity of tumour cells to therapeutics. Furthermore, multiple intracellular signalling pathways prove sensitive to the mechanical properties of the microenvironment. It appears the increased stiffness is unlikely to be caused by increased stiffness of the tumour cells themselves. However, there are indications that tumours display a higher cell density, making them more rigid. In addition, increased matrix deposition in the tumour, as well as increased interstitial fluid pressure may account for the increased stiffness of tumours. Overall, tumour mechanics are significantly different from normal tissue. Therefore, this feature should be further explored for use in cancer prevention, detection and treatment.
The hypoxia-inducible factor (HIF)-1 pathway can stimulate tumor cell migration and metastasis. Furthermore, hypoxic tumors are associated with a poor prognosis. Besides the HIF-1 pathway, the ...unfolded protein response (UPR) is also induced by hypoxic conditions. The PKR-like ER kinase (PERK)/activating transcription factor 4 (ATF4)-arm of the UPR induces expression of lysosomal-associated membrane protein 3 (LAMP3), a factor that has been linked to metastasis and poor prognosis in solid tumors. In this study the role of UPR-induced LAMP3 in hypoxia-mediated migration of breast cancer cells was examined.
A number of in vitro metastasis models were used to study the migration and invasion of MDA-MB-231 breast cancer cells under hypoxic conditions. PERK, ATF4 and their downstream factor LAMP3 were knocked down to examine their role in cell migration. In addition, multicellular tumor spheroids were used to study the involvement of the tumor microenvironment in invasion.
Using transwell assays, migration of different breast cancer cell lines was assessed. A direct correlation was found between cell migration and baseline LAMP3 expression. Furthermore, moderate hypoxia (1% O2) was found to be optimal in stimulating migration of MDA-MB-231 cells. siRNA mediated knockdown of PERK, ATF4 and LAMP3 reduced migration of cells under these conditions. Using gap closure assays, similar results were found. In a three-dimensional invasion assay into collagen, LAMP3 knockdown cells showed a diminished capacity to invade compared to control cells when collectively grown in multicellular spheroids.
Thus, the PERK/ATF4/LAMP3-arm of the UPR is an additional pathway mediating hypoxia-induced breast cancer cell migration.
•Radiotherapy affects immune populations in the TME, including MDSCs.•Conventional fractionated radiation schedules are associated with MDSC recruitment.•Radiotherapy, inflammation and hypoxia play a ...role in MDSC function and recruitment.•Both MDSC-intrinsic and -extrinsic STING signaling are able to alter MDSC behavior.•Future studies should focus on elucidating a potential role of cGAS in MDSC function.
Myeloid derived suppressor cells (MDSCs) are a highly heterogeneous population of immature immune cells with immunosuppressive functions that are recruited to the tumor microenvironment (TME). MDSCs promote tumor growth and progression by inhibiting immune effector cell proliferation and function. MDSCs are affected by both novel anti-cancer therapies targeting the immune system to promote anti-tumor immunity, as well as by conventional treatments such as radiotherapy. Following radiotherapy, cytoplasmic double stranded DNA stimulates the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, resulting in type I interferon production. Effectiveness of radiotherapy and cGAS/STING signaling are closely intertwined: activation of cGAS and STING is key to generate systemic anti-tumor immunity after irradiation. This review focuses on how radiotherapy and cGAS/STING signaling in MDSCs and/or tumor cells impact MDSC recruitment, expansion and function. The influence of conventional and ablative radiotherapy treatment schedules, inflammatory response following radiotherapy, and hypoxia are discussed as MDSC modulators.
TRPM7 encodes a Ca2+-permeable nonselective cation channel with kinase activity. TRPM7 has been implicated in control of cell adhesion and migration, but whether TRPM7 activity contributes to cancer ...progression has not been established. Here we report that high levels of TRPM7 expression independently predict poor outcome in breast cancer patients and that it is functionally required for metastasis formation in a mouse xenograft model of human breast cancer. Mechanistic investigation revealed that TRPM7 regulated myosin II-based cellular tension, thereby modifying focal adhesion number, cell-cell adhesion and polarized cell movement. Our findings therefore suggest that TRPM7 is part of a mechanosensory complex adopted by cancer cells to drive metastasis formation.
Human papillomavirus negative (HPV-ve) head and neck squamous cell carcinoma (HNSCC) has a poor prognosis compared with HPV+ve HNSCCs. Expression of p16 in HPV+ve HNSCC is thought to mediate ...radiosensitivity via inhibition of cyclin-dependent kinase (CDK) 4/6. We used a clinically approved CDK4/CDK6 inhibitor, palbociclib, and assessed its effect on radiosensitivity in HNSCC.
The effect of palbociclib on radiosensitivity was determined in HPV-ve and HPV+ve HNSCC cell lines using colony survival assays, immunofluorescent staining of repair proteins, homologous recombination assays, cell cycle, and metaphase spread analyses.
Only HPV-ve HNSCC cells were radiosensitized by palbociclib, which also occurred at hypoxic levels associated with radioresistance. Palbociclib led to decreased induction of BRCA1 and RAD51 after irradiation. Homologous recombination was diminished and repair of radiation-induced DNA damage was delayed in the presence of palbociclib, leading to increased chromosomal damage. Failure to repair radiation-induced damage led to cell death as a result of mitotic catastrophe.
Here, we highlight a therapeutic strategy to improve the radiosensitivity of HPV-ve HNSCC, a patient group that has an unmet and urgent need for improved radiation therapy efficacy.
As tumors grow, they upregulate glycolytic and oxidative metabolism to support their increased and altered energetic demands. These metabolic changes have major effects on the tumor microenvironment. ...One of the properties leading to this aberrant metabolism is hypoxia, which occurs when tumors outgrow their often-chaotic vasculature. This scarcity of oxygen is known to induce radioresistance but can also have a disrupting effect on the antitumor immune response. Hypoxia inhibits immune effector cell function, while immune cells with a more suppressing phenotype become more active. Therefore, hypoxia strongly affects the efficacy of both radiotherapy and immunotherapy, as well as this therapy combination. Inhibition of oxidative phosphorylation (OXPHOS) is gaining interest for its ability to combat tumor hypoxia, and there are strong indications that this results in a reactivation of the immune response. This strategy decreases oxygen consumption, leading to better oxygenation of hypoxic tumor areas and eventually an increase in immunogenic cell death induced by radio-immunotherapy combinations. Promising preclinical improvements in radio- and immunotherapy efficacy have been observed by the hypoxia-reducing effect of OXPHOS inhibitors and several compounds are currently in clinical trials for their anticancer properties. Here, we will review the pharmacologic attenuation of tumor hypoxia using OXPHOS inhibitors, with emphasis on their impact on the intrinsic antitumor immune response and how this affects the efficacy of (combined) radio- and immunotherapy.
PDF
