PMC:7426526 / 73169-77507 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7426526","sourcedb":"PMC","sourceid":"7426526","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7426526","text":"Future Perspectives\nStudies obtained in the last 5–10 years confirmed the importance and the urgent need of diagnostic screening of the TME not only before the treatment, but also at several stages in the post-therapeutic period. This is within the context of personalized therapies that are based on the idea to identify the best therapeutic approach for the patient. This approach should be based on the tumors molecular signature, involving the TME. The best and the most appropriate therapeutic options, which match each individual patient's requirements will increase the therapeutic efficacy and will cause fewer side effects.\nThe particular value of post-therapeutic local biopsies is that they enable the evaluation of tumor relapse risk on the basis of multivariate biomarkers and also provide information on therapeutically addressable targets within the remaining tumor tissue. In-time detection of tumor-promoting cells, which re-emerge in the post-therapeutic period (Figure 3), will allow an application of the individualized and precise second-line therapy in a timely fashion. Detection of tumor cells with stemness phenotypes will allow for their directed and specific targeting using the second-line treatments, depending on a different mode of action (4, 560). This secondary specific therapy can include, targeted therapies such as e.g., immunotherapies, CAR NK-, and CAR T-cells that mediate a precise eradication of several types of cells: CSCs, CAFs, and/or remaining senescent cells. To increase the specificity and therapeutic outcome and to decrease severe side effects, CAR-based therapeutics are constantly being optimized, as discussed in the section above. Special needs are: improvement of target specificity in combination with decreased off-target effects. In addition, secondary therapies could also include senolytic drugs that selectively kill senescent cells as it was discussed in a recent comprehensive review by Short et al. (599). These therapies cause very low or minor side-effects after their administration (599). In the post-therapeutic period, however, it is important to focus on the biomarkers of CSCs as well as the biomarkers of senescent tumor cells, tumor-promoting SASP molecules, CAFs and TAMs. These cells and molecules strongly influence tumor relapse and their monitoring and their in-time elimination is crucial (Figure 3). As currently available blood test systems are not sensitive enough to detect local changes in the TME, other methods for instance local biopsies and subsequent multivariant analysis of obtained tissues should be used whenever possible and even after many years upon the first-line therapy (Figure 3).\nThe analysis of multivariant biomarker, however is not only of importance within the post-therapeutic situation. A detailed understanding of the tumor composition before the treatment could allow straight forward first line therapies (Figure 4). Target analysis includes CSCs, CAFs, tumors cells and TAMs, and other tumor-promoting cells. Therapeutic options such as chemotherapy and radiotherapy in combination with small molecules and immunotherapies (CAR cells) could tremendously improve the outcome of the first-line approaches and predict relapses (Figure 4). Combinations already in the first-line therapy are especially required in advanced stages of malignant disease.\nIn conclusion, our review gives an overview of the most important biomarkers of CSCs in the TME. Furthermore, we underline the value of local biopsies and precise diagnostics and screening of biomarkers in both pre- and post-therapeutic situations (Figures 3, 4). We suggest the implementation of those strategies in the first and second-line personalized therapy required to eradicate the remaining tumor-promoting senescent tumor cells, CAFs, TAMs, and finally CSCs to protect from tumor recurrence.\nThe high costs are one point of contention regarding the biopsies and their analysis as well as the implementation of immunotherapies into the first and secondary line targeted therapies. However, considering the costs for therapies, comprising resection, and medication strategies, as well as the patient's sufferings due to a re-emerged full-blown cancer, the targeted therapy will help to save the patients and clinics from high personnel, emotional, and medicinal costs.","divisions":[{"label":"title","span":{"begin":0,"end":19}},{"label":"p","span":{"begin":20,"end":632}},{"label":"p","span":{"begin":633,"end":2683}},{"label":"p","span":{"begin":2684,"end":3361}},{"label":"p","span":{"begin":3362,"end":3863}}],"tracks":[{"project":"TEST0","denotations":[{"id":"32849491-178-183-3396688","span":{"begin":1271,"end":1272},"obj":"[\"29681949\"]"},{"id":"32849491-181-188-3396689","span":{"begin":1274,"end":1277},"obj":"[\"28397828\"]"},{"id":"32849491-176-183-3396690","span":{"begin":1966,"end":1969},"obj":"[\"30737084\"]"},{"id":"32849491-81-88-3396691","span":{"begin":2053,"end":2056},"obj":"[\"30737084\"]"}],"attributes":[{"subj":"32849491-178-183-3396688","pred":"source","obj":"TEST0"},{"subj":"32849491-181-188-3396689","pred":"source","obj":"TEST0"},{"subj":"32849491-176-183-3396690","pred":"source","obj":"TEST0"},{"subj":"32849491-81-88-3396691","pred":"source","obj":"TEST0"}]},{"project":"MyTest","denotations":[{"id":"32849491-29681949-34971068","span":{"begin":1271,"end":1272},"obj":"29681949"},{"id":"32849491-28397828-34971069","span":{"begin":1274,"end":1277},"obj":"28397828"},{"id":"32849491-30737084-34971070","span":{"begin":1966,"end":1969},"obj":"30737084"},{"id":"32849491-30737084-34971071","span":{"begin":2053,"end":2056},"obj":"30737084"}],"namespaces":[{"prefix":"_base","uri":"https://www.uniprot.org/uniprot/testbase"},{"prefix":"UniProtKB","uri":"https://www.uniprot.org/uniprot/"},{"prefix":"uniprot","uri":"https://www.uniprot.org/uniprotkb/"}],"attributes":[{"subj":"32849491-29681949-34971068","pred":"source","obj":"MyTest"},{"subj":"32849491-28397828-34971069","pred":"source","obj":"MyTest"},{"subj":"32849491-30737084-34971070","pred":"source","obj":"MyTest"},{"subj":"32849491-30737084-34971071","pred":"source","obj":"MyTest"}]},{"project":"2_test","denotations":[{"id":"32849491-29681949-34971068","span":{"begin":1271,"end":1272},"obj":"29681949"},{"id":"32849491-28397828-34971069","span":{"begin":1274,"end":1277},"obj":"28397828"},{"id":"32849491-30737084-34971070","span":{"begin":1966,"end":1969},"obj":"30737084"},{"id":"32849491-30737084-34971071","span":{"begin":2053,"end":2056},"obj":"30737084"}],"attributes":[{"subj":"32849491-29681949-34971068","pred":"source","obj":"2_test"},{"subj":"32849491-28397828-34971069","pred":"source","obj":"2_test"},{"subj":"32849491-30737084-34971070","pred":"source","obj":"2_test"},{"subj":"32849491-30737084-34971071","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"TEST0","color":"#9c93ec","default":true},{"id":"MyTest","color":"#a3ec93"},{"id":"2_test","color":"#ec93bd"}]}]}}