Patient-derived xenografts, the cancer stem cell paradigm, and cancer pathobiology in the 21st century

Abstract

Cancer is a heterogeneous disease manifest in many forms. Tumor histopathology can differ significantly among patients and cellular heterogeneity within tumors is common. A primary goal of cancer biologists is to better understand tumorigenesis and cancer progression; however, the complex nature of tumors has posed a substantial challenge to unlocking cancer's secrets. The cancer stem cell (CSC) paradigm for the pathobiology of solid tumors appropriately acknowledges phenotypic and functional tumor cell heterogeneity observed in solid tumors and accounts for the disconnect between drug approval based on response and the general inability of approved therapies to meaningfully impact survival due to their failure to eradicate these most important of cellular targets. First proposed to exist decades ago, CSC have only recently begun to be precisely identified due to technical advancements that facilitate identification, isolation, and interrogation of distinct tumor cell subpopulations with differing ability to form and perpetuate tumors. Precise identification of CSC populations and the complete hierarchy of cells within solid tumors will facilitate more accurate characterization of patient subtypes and ultimately contribute to more personalized and effective therapies. Rapid advancement in the understanding of tumor biology as it exists in patients requires cooperation among institutions, surgeons, pathologists, cancer biologists and patients alike, primarily because this translational research is best done with patient-derived tissue grown in the xenograft setting as patient-derived xenografts. This review calls for a broader change in the approaches taken to study cancer pathobiology, highlights what implications the CSC paradigm has for pathologists and cancer biologists alike, and calls for greater collaboration between institutions, physicians and scientists in order to more rapidly advance our collective understanding of cancer.

Establishment of a novel human medulloblastoma cell line characterized by highly aggressive stem-like cells

“…In the case of pediatric brain tumors such as medulloblastoma, only a few cell lines have been more extensively used in research (Xu et al 2012(Xu et al , 2015. Medulloblastoma, however, comprise a group of highly heterogeneous tumors, as revealed by recent gene expression profiling and exome sequencing studies (Kool et al 2012;Baron 2012;Mardis 2012;Williams et al 2013). Current molecular subtypes of medulloblastoma are differentially associated with treatment response, frequency of metastasis, and survival rate (Kool et al 2012;Northcott et al 2012;Ramaswamy et al 2013b).…”

The Role of Biomaterials on Cancer Stem Cell Enrichment and Behavior

“…In many cases, animal models also fail to accurately predict clinical outcomes. 23 The results are often convoluted with complex sets of variables, such as animal-to-animal variations and the role of an intact immune system which is present in human patients but not properly modeled in most xenograft models. These and many other factors often lead to poor translation from preclinical to clinical studies.…”

Cancer stem cells and addicted cancer cells

“…As discussed, a tumor is comprised of cells that exhibit distinct capacities in proliferation and differentiation due to the process of clonal selection [1,15]. Populations of supporting, dividing, differentiating and degenerating cells form an integrated tumor mass [17]. Intratumoral heterogeneity and its extent has been demonstrated in a study on advanced human colorectal adenocarcinoma, where 67% of the analyzed tumors were heterogeneous for at least 1 mutation, with 2 until 6 different clonal genotypes per tumor [18].…”

“…Where stem cells in normal tissues are defined as undifferentiated cells with the capacity to produce the specialized cells that compromise the tissue, CSCs define specialized populations of cells in tumor tissue that are responsible for the growth and recurrence of the tumor [17,38,39]. During the evolution of a malignant tumor, alterations that result from mutations and epigenetic changes lead to deregulated cell production and clonal expansion.…”

“…Several characteristics are shared by CSCs and normal adult stem cells, including the expression of primitive stem cell markers and human telomere reverse transcriptase (hTERT) [40]. Moreover, CSCs have an increased expression multidrug resistance transporters and DNA damage repair enzymes [17].…”