Determinates of tumor response to radiation: Tumor cells, tumor stroma and permanent local control

Abstract

Background and Purpose The causes of tumor response variation to radiation remain obscure, thus hampering the development of predictive assays and strategies to decrease resistance. The present study evaluates the impact of host tumor stromal elements and the in vivo environment on tumor cell kill, and relationship between tumor cell radiosensitivity and the tumor control dose. Material and Methods Five endpoints were evaluated and compared in a radiosensitive DNA double-strand break repair-defective (DNA-Pkcs−/−) tumor line, and its DNA-PKcs repair competent transfected counterpart. In vitro colony formation assays were performed on in vitro cultured cells; on cells obtained directly from tumors, and on cells irradiated in situ. Permanent local control was assessed by the TCD50 assay. Vascular effects were evaluated by functional vascular density assays. Results The fraction of repair competent and repair deficient tumor cells surviving radiation did not substantially differ whether irradiated in vitro, i.e., in the absence of host stromal elements and factors, from the fraction of cells killed following in vivo irradiation. Additionally, the altered tumor cell sensitivity resulted in a proportional change in the dose required to achieve permanent local control. The estimated number of tumor cells per tumor, their cloning efficiency and radiosensitivity, all assessed by in vitro assays, were used to predict successfully, the measured tumor control doses. Conclusion The number of clonogens per tumor and their radiosensitivity govern the permanent local control dose.

Whole‐tumor histogram analysis of monoexponential and advanced diffusion‐weighted imaging for sinonasal malignant tumors: Correlations with histopathologic features

“…For instance, patients with high tumor cellularity commonly suffer from high local recurrence and poor prognosis and therefore should be identified early. More important, patients with stroma‐rich tumors have been reported to suffer from radiotherapy resistance and increased metastatic risk . Thus, the tumor‐stroma ratio (stromal fraction) has recently been recognized as an independent, poor prognostic factor for esophageal, breast, and colon cancers .…”

A voxel‐based multiscale model to simulate the radiation response of hypoxic tumors

“…In the latter, most of the in vivo studies indicate a minor role of radiation-induced vascular damage in tumors as a determinant of response for the endpoint of permanent local control. [42][43][44] Moreover, the underlying mechanisms are highly complex and most likely different at different dose levels. 45 Although the radiosensitivity of capillary cells could in principle be implemented in a similar way as for tumor cells, the underlying biological mechanisms remain still rather unclear.…”

Targeting Enox1 in tumor stroma increases the efficacy of fractionated radiotherapy

“…Tumor-bearing legs were made totally anoxic/hypoxic by clamping the legs for 5 min and irradiating under clamped conditions. Quantification of TCD values led Budach et al [36] and Li et al [37] to conclude that the number of tumor progenitor cells and their intrinsic radiosensitivity were the major determinants of local tumor control, with little contribution from host stroma. However, a caveat to this interpretation is the potentially confounding effect of extreme hypoxia, a consequence of clamping, on DNA repair capacity.…”