Cell Differentiation and Heterogeneity in Spheroid Culture
Rolf Bjerkvig in Spheroid Culture in Cancer Research, 2017
Many experiments indicate that spheroids of tumor cells also exhibit more in vivo-like differentiation than do monolayers. To confirm and further refine these findings, the definition of differentiation by the pathologist’s criteria for grading of tumors and additional support by immunohistochemistry, biochemistry, and molecular biology is necessary. Cells from homogeneous monolayer cell populations often change to a heterogenous population of cells in spheroids by criteria such as cell shape, size, or distribution of organelles. Heterogeneity as described here within a cloned cell line indicates phenotypic variations due to cell-cycle state, cell-cell interaction, amount of extracellular matrix components, and other microenvironmental factors. This type of heterogeneity is called “secular heterogeneity” by Heppner19 to distinguish it from clonal tumor heterogeneity, and it is known to be an important variable for tumor therapy.20 It is similar to the heterogeneity seen in a poorly vascularized part of an in vivo tumor,21 or to that in a not-yet-vascularized micrometastatic focus, or to that of a cluster of tumor cells in malignant effusions,22 and it can be studied easily in spheroids.
The Molecular Genetics OF DNA Methylation in Colorectal Cancer
Leonard H. Augenlicht in Cell and Molecular Biology of Colon Cancer, 2019
Two phenomena became apparent from this larger study. First, there is substantial heterogeneity of the hypomethylation patterns, no matter how one addresses that question. There is heterogeneity in the methylation pattern of a given gene from patient to patient and also from tumor to tumor for a given gene, when there are multiple lesions from the same patient. For example, one patient with two cancers and two polyps showed differences in methylation from gene to gene, and from site to site for a given gene.28 We also sampled multiple times from a given tumor, and at this level of dissection, we were unable to discern any difference in the methylation pattern. Therefore, we conclude that heterogeneity is a relatively early event in the development of a given neoplastic lesion or that there is intermingling of cells within that lesion. Tumor heterogeneity is a substantial problem in human cancer. Most solid tumors are capable of escaping a given chemotherapeutic or radiation protocol, as subpopulations of cells are resistant to that agent. This is the first demonstration at the genomic level of DNA heterogeneity in tumors, and it is intriguing to speculate that this may underlie at least part of the tumor heterogeneity seen at the phenotypic level.
How to Validate Histochemical Techniques as Predictors of Hormonal Response
P. Pertschuk Louis, Lee Sin Hang in Localization of Putative Steroid Receptors, 2018
The evaluation of steroid receptors in human breast cancer has become important in the management of breast cancerpatients, both in guiding treatment decisions and as a prognostic factor.12 The difficulties encountered with expensive and meticulous techniques such as the biochemical assay have stimulated several groups13-16 to supplement this method by histochemical techniques which attempt to localize estrogen receptors at the cellular level. In this report, we have not addressed what these histochemical tracers are localizing, but we have examined the correlation between histochemical and biochemical techniques, and, most important, the ability of the histochemical technique to predict response to therapy. Tumor heterogeneity for biological markers is a well-known phenomenon in cancer.18 It becomes apparent, using histochemical techniques, that in any breast cancer there are mixtures of positive and negative cells. The combination of histochemical and biochemical receptor techniques may help to overcome the problems posed by this tumor heterogeneity.
Prognostic significance of proteomics and multi-omics studies in renal carcinoma
Published in Expert Review of Proteomics, 2020
Francesca Raimondo, Marina Pitto
Tumor heterogeneity may be defined as the molecular, morphological, and behavioral variability that cancer cells display within a single tumor. It depends on genetic, epigenetic, and microenvironmental factors and presents a challenge for cancer diagnosis and therapy [16]. However, it may well be responsible for the failure to find suitable candidate markers able to help in assigning a meaningful prognosis to each patient. This heterogeneity is characteristic of virtually any solid tumor, but many observations concur in showing that it is particularly marked in the case of RCC. This may explain why currently used methodologies in diagnostic pathology often fail in indicating the correct prognosis, lacking the capability to discern deeper genotypic and subtler phenotypic differences among individual patients.
HIF-1α affects sensitivity of murine squamous cell carcinoma to boron neutron capture therapy with BPA
Published in International Journal of Radiation Biology, 2021
Yu Sanada, Takushi Takata, Hiroki Tanaka, Yoshinori Sakurai, Tsubasa Watanabe, Minoru Suzuki, Shin-ichiro Masunaga
Tumor heterogeneity (existence of tumor cells that display distinct phenotypes) is well described in solid tumors, and is considered to influence response to cancer therapy (Fisher et al. 2013). SCC VII and SCC VII Hif-1α-deficient tumor tissues appeared to contain similar amounts of BPA (Figure 4(A)). However, the biological effects of BNCR may be dependent on the intracellular concentration and localization of the 10B-carrier due to the short range of α particles and 7Li ions. Since a hypoxic environment exists in solid tumor tissues (e.g. due to an abnormal vasculature), SLC7A5 protein expression may have been down-regulated and BPA uptake inhibited in intra-tumor hypoxic regions, which may partly explain the differences observed in cell survival between SCC VII and SCC VII Hif-1α-deficient cells from BPA-administered mice (Figure 4(B)).
Evaluation of programmed cell death protein 1 (PD-1) expression as a prognostic biomarker in patients with clear cell renal cell carcinoma
Published in OncoImmunology, 2018
Kyu Seo Kim, Rishi R. Sekar, Dattatraya Patil, Michelle A. Dimarco, Haydn T. Kissick, Mehmet A. Bilen, Adeboye O. Osunkoya, Viraj A. Master
Tumor heterogeneity further complicates the matter. A multi-region sequencing study showed that spatially separated samples from the same RCC tumor underwent a number of convergent and divergent mutations, some of which are signatures of good prognosis and some of poor prognosis.45 Supporting that finding, studies on variability of PD-L1 expression within tumor and between primary and metastatic sites have been inconclusive, neither showing dependence or independence.46,47 It remains to be determined whether sampling multiple sites adds value to clinical decision making or where in the tumor spatially (invasive margin versus tumor core) best represents the tumor microenvironment. A way to potentially circumvent the tumor heterogeneity issue is to measure systemic markers circulating in the blood, and to that end, an association between level of soluble PD-L1 circulating in serum and survival has been reported in clear cell RCC patients.48