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PubMed2026

Pan-cancer characterization of HMGA1 reveals its oncogenic role in tumor microenvironment and stemness: functional validation in pancreatic cancer migration and invasion.

BACKGROUND: HMGA1 is a chromatin-associated oncogenic factor implicated in tumor progression, epithelial-mesenchymal transition (EMT), stemness, and metastasis. However, its pan-cancer expression and prognostic patterns, epigenetic activation, and relationship with malignant-cell stemness/plasticity and tumor microenvironment (TME) remodeling in pancreatic adenocarcinoma (PAAD) remain incompletely defined. This study aimed to systematically characterize HMGA1 across cancers and clarify its clinical and biological relevance in PAAD. METHODS: Pan-cancer transcriptomic, clinical, genetic, methylation, immune, and stemness data were integrated from multiple public databases. PAAD single-cell RNA sequencing data were analyzed to localize HMGA1 expression, infer malignant-cell pseudotime, calculate a stemness module score, and assess ligand-receptor communication using CellChat. Public HMGA1-knockdown RNA sequencing data were reanalyzed to evaluate transcriptional remodeling. The Cancer Genome Atlas (TCGA)-PAAD expression and methylation data were used to assess TME-remodeling, immune-suppression, stemness/plasticity, cytokine/chemokine, checkpoint, and promoter-methylation features. HMGA1 expression and function were further examined using immunohistochemistry (IHC), quantitative real-time polymerase chain reaction, Western blotting, wound-healing assays, and Transwell migration and invasion assays. RESULTS: HMGA1 was upregulated in most tumor types, and high expression was associated with unfavorable survival in multiple cancers, including PAAD. In PAAD, HMGA1 was enriched in malignant epithelial cells and positively correlated with pseudotime (Spearman's rho =0.594), while the stemness module score increased along pseudotime (rho =0.748). HMGA1-high malignant cells showed markedly stronger CellChat-inferred outgoing communication, predominantly involving extracellular matrix (ECM)-receptor, adhesion-related, and selected immunomodulatory ligand-receptor axes. HMGA1 knockdown was associated with broad remodeling of EMT, TGF-β, Hedgehog, IL6/JAK/STAT3, KRAS, and cancer stem cell/stemness-related programs rather than uniform suppression of these programs. HMGA1 promoter methylation was inversely correlated with HMGA1 expression (rho =-0.633) and the TME-remodeling score (rho =-0.347). HMGA1 was associated with selected mediators, including PPIA, PLAU, ANXA1, LGALS9, TGFB1, CD276, and CD47, but not with a generalized checkpoint-high phenotype. Functionally, HMGA1 knockdown significantly reduced pancreatic cancer (PC) cell migration and invasion. CONCLUSIONS: These findings support an association-based model in which promoter hypomethylation-associated HMGA1 activation is linked to malignant epithelial stemness/plasticity, ECM/adhesion-dominant TME remodeling, selected immunomodulatory programs, and aggressive PAAD phenotypes. Further mechanistic and clinical validation is required before HMGA1 can be used for therapeutic stratification or immunotherapy-response prediction.

HMGA1↗

PubMed2006

Stem cells: tissue regeneration and cancer.

Regenerative medicine is the promised paradigm of replacement and repair of damaged or senescent tissues. As the building blocks for organ development and tissue repair, stem cells have unique and wide-ranging capabilities, thus delineating their potential application to regenerative medicine. The recognition that consistent patterns of molecular mechanisms drive organ development and postnatal tissue regeneration has significant implications for a variety of pediatric diseases beyond replacement biology. The observation that organ-specific stem cells derive all of the differentiated cells within a given tissue has led to the acceptance of a stem cell hierarchy model for tissue development, maintenance, and repair. Extending the tissue stem cell hierarchical model to tissue carcinogenesis may revolutionize the manner in which we conceptualize cancer therapeutics. In this review, the clinical promise of these technologies and the emerging concept of "cancer stem cells" are examined. A basic understanding of stem cell biology is paramount to stay informed of this emerging technology and the accompanying research in this area with the potential for clinical application.

Animals↗

PubMed2005

Wnt signaling in stem cells and non-small-cell lung cancer.

Evidence suggests that stem cells may be the source of mutant cells that cause cancers to develop and proliferate. Wnt signaling has been shown to promote self-renewal in gut epithelial and hematopoietic stem cells and to trigger critical pathways in carcinogenesis. In this review, we highlight the progress in understanding how the Wnt pathway contributes to stem cell maintenance and its role in lung carcinogenesis. Although the function of stem cells in solid tumor development is unclear, the Wnt pathway's role in determining the fate and self-renewal potential of cancer stem cells suggests a critical role in carcinogenesis and that developing drugs to inhibit this pathway may be of therapeutic interest.

Carcinoma, Non-Small-Cell Lung↗

PubMed2005

Interpreting epithelial cancer biology in the context of stem cells: tumor properties and therapeutic implications.

Over 90% of all human neoplasia is derived from epithelia. Significant progress has been made in the identification of stem cells of many epithelia. In general, epithelial stem cells lack differentiation markers, have superior in vivo and in vitro proliferative potential, form clusters in association with a specialized mesenchymal environment (the 'niche'), are located in well-protected and nourished sites, and are slow-cycling and thus can be experimentally identified as 'label-retaining cells'. Stem cells may divide symmetrically giving rise to two identical stem cell progeny. Any stem cells in the niche, which defines the size of the stem cell pool, may be randomly expelled from the niche due to population pressure (the stochastic model). Alternatively, a stem cell may divide asymmetrically yielding one stem cell and one non-stem cell that is destined to exit from the stem cell niche (asymmetric division model). Stem cells separated from their niche lose their stemness, although such a loss may be reversible, becoming 'transit-amplifying cells' that are rapidly proliferating but have a more limited proliferative potential, and can give rise to terminally differentiated cells. The identification of the stem cell subpopulation in a normal epithelium leads to a better understanding of many previously enigmatic properties of an epithelium including the preferential sites of carcinoma formation, as exemplified by the almost exclusive association of corneal epithelial carcinoma with the limbus, the corneal epithelial stem cell zone. Being long-term residents in an epithelium, stem cells are uniquely susceptible to the accumulation of multiple, oncogenic changes giving rise to tumors. The application of the stem cell concept can explain many important carcinoma features including the clonal origin and heterogeneity of tumors, the occasional formation of tumors from the transit amplifying cells or progenitor cells, the formation of precancerous 'patches' and 'fields', the mesenchymal influence on carcinoma formation and behavior, and the plasticity of tumor cells. While the concept of cancer stem cells is extremely useful and it is generally assumed that such cells are derived from normal stem cells, more work is needed to identify and characterize epithelial cancer stem cells, to address their precise relationship with normal stem cells, to study their markers and their proliferative and differentiation properties and to design new therapies that can overcome their unusual resistance to chemotherapy and other conventional tumor modalities.

Animals↗

PubMed1990

[Peripheral blood stem cell autografts in pediatric cancer].

Harvest of peripheral blood stem cells (PBSC) for autografts is a safe, reliable procedure with low morbidity in children with cancer, and cryopreserved PBSC are useful in reducing cytopenia following marrow-ablative chemotherapy. The colony forming unit granulocyte/macrophage (CFU-GM) content of the thawed grafts is an important determinant of hematopoietic recovery after PBSC autografts. The possible value of high-dose chemotherapy without total body irradiation and PBSCT compared to intensified chemotherapy in the treatment of children with very high-risk lymphoid malignant disorders was reported.

Adolescent↗

PubMed2004

Stem cells, aging, and cancer: inevitabilities and outcomes.

Given the unique abilities of a stem cell to self-renew, differentiate, and proliferate, it is no wonder that they are critically important to an organism during development and to maintain homeostasis. Likewise, when something goes awry within a stem cell, it is likely to have far-reaching effects, since stem cells persist throughout the lifetime of the individual. Two significant biological phenomena that involve stem cells are the inevitable process of aging and a major health issue whose incidence increases with aging: cancer. In this review, we summarize evidence and theories concerning these two stem cell processes. The inability of stem cells to be passaged indefinitely in mice and the data supporting regular replication of the quiescent stem cell pool are discussed. Further, the current evidence indicating a stem cell origin of acute myeloid leukemia, including examples from both experimental mouse models and human clinical samples, is evaluated. Finally, we propose a model in which aging of the stem cell population of the hematopoietic system in particular can create conditions that are permissive to leukemia development; in fact, we suggest that aging is a secondary event in leukemogenesis.

Acute Disease↗

PubMed2004

Prostate stem cell antigen (PSCA) expression in human prostate cancer tissues: implications for prostate carcinogenesis and progression of prostate cancer.

OBJECTIVE: Prostate stem cell antigen (PSCA) is a recently defined homolog of the Thy-1/Ly-6 family of glycosylphosphatidylinositol (GPI)-anchored cell surface antigens. The objective of the present study was to examine the expression status of PSCA protein and mRNA in clinical specimens of human prostate cancer (PCa) and to validate it as a potential molecular target for diagnosis and treatment of PCa. METHODS: Immunohistochemical (IHC) and in situ hybridization (ISH) analyses of PSCA expression were simultaneously performed on paraffin-embedded sections of 20 benign prostatic hyperplasia (BPH), 20 prostatic intraepithelial neoplasm (PIN) and 48 prostate cancer (PCa) tissues, including 9 androgen-independent prostate cancers. The level of PSCA expression was semiquantitatively scored by assessing both the percentage and intensity of PSCA-positive staining cells in the specimens. We then compared the PSCA expression between BPH, PIN and PCa tissues and analyzed the correlations of PSCA expression level with pathological grade, clinical stage and progression to androgen-independence in PCa. RESULTS: In BPH and low grade PIN, PSCA protein and mRNA staining were weak or negative and less intense and uniform than that observed in high grade PIN (HGPIN) and PCa. Moderate to strong PSCA protein and mRNA expression were noted in 8 of 11 (72.7%) HGPIN and in 40 of 48 (83.4%) PCa specimens examined by IHC and ISH analyses, and their statistical significance was compared with BPH (20%) and low-grade PIN (22.2%) specimens (P < 0.05). The expression level of PSCA increased with a higher Gleason grade, advanced stage and progression to androgen-independence (P < 0.05). In addition, IHC and ISH staining revealed a high degree of correlation between PSCA protein and mRNA overexpression. CONCLUSIONS: Our data demonstrate that PSCA as a new cell surface marker is overexpressed in a majority of cases of human PCa. PSCA expression correlates positively with adverse tumor characteristics, such as increasing pathological grade (poor cell differentiation), worsening clinical stage and androgen-independence and speculatively with prostate carcinogenesis. PSCA may possess prognostic utility and may be a promising molecular target for diagnosis and treatment of PCa.

Aged↗

PubMed2004

Prostate stem cell antigen (PSCA) expression in human prostate cancer tissues and its potential role in prostate carcinogenesis and progression of prostate cancer.

BACKGROUND: Prostate stem cell antigen (PSCA) is a recently defined homologue of the Thy-1/Ly-6 family of glycosylphosphatidylinositol (GPI)-anchored cell surface antigens. The purpose of the present study was to examine the expression status of PSCA protein and mRNA in clinical specimens of human prostate cancer (Pca) and to validate it as a potential molecular target for diagnosis and treatment of Pca. MATERIALS AND METHODS: Immunohistochemical (IHC) and in situ hybridization (ISH) analyses of PSCA expression were simultaneously performed on paraffin-embedded sections from 20 benign prostatic hyperplasia (BPH), 20 prostatic intraepithelial neoplasm (PIN) and 48 prostate cancer (Pca) tissues, including 9 androgen-independent prostate cancers. The level of PSCA expression was semiquantitatively scored by assessing both the percentage and intensity of PSCA-positive staining cells in the specimens. Then compared PSCA expression between BPH, PIN and Pca tissues and analysed the correlations of PSCA expression level with pathological grade, clinical stage and progression to androgen-independence in Pca. RESULTS: In BPH and low grade PIN, PSCA protein and mRNA staining were weak or negative and less intense and uniform than that seen in HGPIN and Pca. There were moderate to strong PSCA protein and mRNA expression in 8 of 11 (72.7%) HGPIN and in 40 of 48 (83.4%) Pca specimens examined by IHC and ISH analyses, with statistical significance compared with BPH (20%) and low grade PIN (22.2%) samples (p < 0.05, respectively). The expression level of PSCA increased with high Gleason grade, advanced stage and progression to androgen-independence (p < 0.05, respectively). In addition, IHC and ISH staining showed a high degree of correlation between PSCA protein and mRNA overexpression. CONCLUSIONS: Our data demonstrate that PSCA as a new cell surface marker is overexpressed by a majority of human Pca. PSCA expression correlates positively with adverse tumor characteristics, such as increasing pathological grade (poor cell differentiation), worsening clinical stage and androgen-independence, and speculatively with prostate carcinogenesis. PSCA protein overexpression results from upregulated transcription of PSCA mRNA. PSCA may have prognostic utility and may be a promising molecular target for diagnosis and treatment of Pca.

Duplicate Publication↗

PubMed2005

Role of depression as a predictor of mortality among cancer patients after stem-cell transplantation.

PURPOSE: To determine the association between depression and survival among cancer patients at 1, 3, and 5 years after stem-cell transplantation (SCT). PATIENTS AND METHODS: This was a prospective cohort study of 199 hematologic cancer patients who survived longer than 90 days after SCT and who were recruited in a University-based hospital between July 1994 and August 1997. Patients received a psychiatric assessment at four consecutive time points during hospitalization for SCT, yielding a total of 781 interviews. Depression diagnoses were determined on the basis of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. RESULTS: Eighteen (9.0%) and 17 patients (8.5%) met criteria for major and minor depression, respectively. Multivariate Cox regression models found major depression to be predictive of higher 1-year (hazard ratio [HR], 2.59; 95% CI, 1.21 to 5.53; P = .014) and 3-year mortality (HR, 2.04; 95% CI, 1.03 to 4.02; P = .041) but not 5-year mortality (HR, 1.48; 95% CI, 0.76 to 2.87; P = .249). Minor depression had no effect on any mortality outcome. Other multivariate significant predictors of higher mortality were higher regimen toxicity in the 1-, 3-, and 5-year models; older age and acute lymphoblastic leukemia in the 3- and 5-year models; chronic myelogenous leukemia in the 3-year model; and lower functional status and intermediate/higher risk status in the 5-year model. Use of peripheral-blood stem cells predicted lower mortality in the 5-year model. CONCLUSION: After adjusting for multiple factors, major depression predicted higher 1- and 3-year mortality among cancer patients after SCT, underscoring the importance of adequate diagnosis and treatment of major depression.

Adolescent↗

PubMed2005

Clinical factors associated with fatigue in haematologic cancer patients receiving stem-cell transplantation.

We have evaluated risk factors associated with fatigue in 220 cancer patients during hospitalization for stem-cell transplantation (SCT). Fatigue was assessed using a validated one-item energy scale and a comprehensive set of fatigue predictors, at hospital admission (baseline), day of SCT, and 7 days and 14 days after SCT. In cross-sectional multivariate analysis, depression was the variable most consistently and strongly associated with fatigue; other factors significantly associated with fatigue at some time during the study included older age, higher education, smoking, lower Karnofsky performance status, loss of appetite, nausea/vomiting, pain, higher regimen-related toxicity, low hemoglobin level, requirement for red blood-cell transfusions, and third year of the study period. In prospective multivariate analysis, baseline depression showed significance or a trend towards significance in its ability to predict subsequent measures of fatigue during hospitalization. Our findings may help to shed light on the mechanisms underlying fatigue and may also guide future interventions.

Adolescent↗

PubMed2001

Reducing mammary cancer risk through premature stem cell senescence.

The reproductive capacity of the mammary epithelial stem cell is reduced coincident with the number of symmetric divisions it must perform. In a study of FVB/N mice with the transgene, WAP-TGFbeta1, we discovered that mammary epithelial stem cells were prematurely aged due to ectopic expression of TGF-beta1. To test whether premature aging of mammary epithelial stem cells would have an impact on susceptibility or resistance to mammary cancer, female littermates from FVB/N x WAP-TGF-beta1 mating were injected with mouse mammary tumor virus (MMTV) at 8-10 weeks of age. A total of 44 females were inoculated, maintained as breeders and observed for tumor development for up to 18 months. Only one mammary tumor appeared in 17 TGF-beta1 females while 15 were collected from 29 wild type sisters. Premalignant mammary epithelial cells in infected glands were identified by transplantation of single cell (1 x 10(5)) suspensions into nulliparous hosts and testing for hyperplastic outgrowth. Although the number of positive takes was significantly reduced with TGF-beta1 cells, both MMTV-infected TGF-beta1 and wild type cells produced hyperplastic outgrowths suggesting that premalignant transformation was achieved in each group. The results suggest a positive correlation between the procreative life-span of mammary epithelial stem cells and mammary cancer risk.

Animals↗

PubMed1998

Prostate stem cell antigen: a cell surface marker overexpressed in prostate cancer.

The identification of cell surface antigens is critical to the development of new diagnostic and therapeutic modalities for the management of prostate cancer. Prostate stem cell antigen (PSCA) is a prostate-specific gene with 30% homology to stem cell antigen 2, a member of the Thy-1/Ly-6 family of glycosylphosphatidylinositol (GPI)-anchored cell surface antigens. PSCA encodes a 123-aa protein with an amino-terminal signal sequence, a carboxyl-terminal GPI-anchoring sequence, and multiple N-glycosylation sites. PSCA mRNA expression is prostate-specific in normal male tissues and is highly up-regulated in both androgen-dependent and -independent prostate cancer xenografts. In situ mRNA analysis localizes PSCA expression in normal prostate to the basal cell epithelium, the putative stem cell compartment of the prostate. There is moderate to strong PSCA expression in 111 of 126 (88%) prostate cancer specimens examined by in situ analysis, including high-grade prostatic intraepithelial neoplasia and androgen-dependent and androgen-independent tumors. Flow cytometric analysis demonstrates that PSCA is expressed predominantly on the cell surface and is anchored by a GPI linkage. Fluorescent in situ hybridization analysis localizes the PSCA gene to chromosome 8q24.2, a region of allelic gain in more than 80% of prostate cancers. A mouse homologue with 70% amino acid identity and similar genomic organization to human PSCA has also been identified. These results support PSCA as a target for prostate cancer diagnosis and therapy.

Amino Acid Sequence↗

PubMed1993

Hyperfractionated radiation therapy (72 Gy) for children with brain stem gliomas. A Childrens Cancer Group Phase I/II Trial.

BACKGROUND: Most children with brain stem gliomas (BSG) die within 18 months of diagnosis. Early experience suggested that hyperfractionated radiation therapy (RT) at a dose of 72 Gy, administered in 1-Gy fractions twice daily, possibly improved disease-free survival for children with BSG. METHODS: To better characterize the toxicity and possible efficacy of this dose and fractionation of RT, 53 assessable children with diffuse intrinsic or malignant BSG were treated. Survival figures also were combined with outcome in 36 patients treated in a previous pilot study. RESULTS: An objective response to treatment was observed in 28 of 53 (53%) patients; a partial response occurred in 7. No child died of treatment-related brain necrosis, although 7 of 53 did have intralesional cystic/necrotic changes within 6 weeks of completion of RT. The overall survival rate for patients in the study was 38% (+/- 6.5) at 1 year, 14% (+/- 5.4) at 2 years, and 8% (+/- 6.5) at 3 years. Leptomeningeal dissemination was observed in 4 of 48 (8%) children who had relapses. A greater than 2-month duration of symptoms before diagnosis was related to a better prognosis. There was no statistical association between any other clinical parameter, neuroradiographic finding, or pathologic finding and outcome. Combined with that in 35 patients treated in the pilot study, the survival rate in 88 children was 14% (+/- 5) at 3 years. CONCLUSIONS: The radiographic response rate is encouraging; however, it cannot be concluded that hyperfractionated RT, at this dose schedule and total dose, is superior to conventional RT.

Adolescent↗

PubMed1999

Fatigue and quality of life in breast cancer patients undergoing autologous stem cell transplantation: a longitudinal comparative study.

As more individuals are being treated for cancer with high-dose therapy and autologous stem cell rescue (ASCR), there is growing interest in treatment side effects and their impact on quality of life. The primary aim of this study was to determine if the severity of fatigue and its impact on quality of life is significantly greater in women undergoing ASCR for breast cancer than in women of similar age with no history of cancer. A group of women being treated with ASCR for breast cancer (n = 31) and a group of women of similar age with no history of cancer (n = 49) participated in this study. Patients completed measures of fatigue and psychosocial functioning prior to treatment, midway through treatment, and toward the end of treatment. Healthy comparison subjects completed the same measures three separate times. Breast cancer patients undergoing ASCR reported significantly more frequent fatigue and more severe fatigue than women with no cancer history. In addition, fatigue had a significantly greater impact on daily functioning and quality of life in patients than in women with no cancer history. Fatigue during ASCR for breast cancer was related to both medical factors (i.e., time since transplant) and psychosocial factors. During ASCR for breast cancer, women experience fatigue which is worse than what is "normally" experienced and which interferes with daily functioning and quality of life. Future research should focus on identifying the biological correlates of fatigue, psychological and physiological mechanisms by which fatigue is produced, and interventions to alleviate fatigue.

Adult↗

PubMed2006

Epigenetic regulation of the expression of the novel stem cell marker CDCP1 in cancer cells.

CDCP1 is a novel stem cell marker that is expressed in several types of cancer. The mechanisms by which CDCP1 expression is regulated, and the clinical implications of this marker, have not been clarified. In this report, we examine the epigenetic regulation of CDCP1 expression in cell lines and clinical samples from patients with breast cancer. Many CpG sequences were localized around the transcription initiation site of CDCP1. These CpG motifs were found to be poorly methylated in cell lines with high levels of CDCP1 expression and heavily methylated in cell lines with low levels of CDCP1 expression. The in vitro methylation of CpG sites decreased CDCP1 promoter activity, and the addition of a demethylating reagent restored activity. In 25 breast cancer samples, an inverse correlation was noted between the CDCP1 expression level and the proportion of methylated to non-methylated CpG sites. Tumours with high-level CDCP1 expression showed higher levels of proliferation, as revealed by immunohistochemical detection of the MIB-1 antigen, than tumours with low-level CDCP1 expression. These findings indicate that the expression of CDCP1 is regulated by methylation of its promoter region in tumours. CDCP1 expression may prove to be useful in the further characterization of cancers.

Adenocarcinoma↗

PubMed2007

Second solid cancers after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: The objective of this study was to establish the incidence and risk factors for the development of second solid cancers after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: The authors reviewed the case files of 926 consecutive patients who underwent allo-HSCT at their institution between 1985 and 2003. RESULTS: Twenty-eight patients developed 30 solid malignancies at a median of 6.8 years after allo-HSCT (range, 0.12-17.3 years) for a 10-year cumulative incidence of 3.1% (95% confidence interval [95% CI], 2-5%; all solid tumors) and 2.3% (95% CI 1-4%; excluding basal cell carcinoma and carcinoma in situ). The risk ratio of developing a second solid malignancy after allografting, compared with the general population of British Columbia adjusted for age and sex, was 1.85 (95% CI, 1.04-3.06; P = .019). In multivariate analysis, recipient age at allo-HSCT >40 years (P = .005) and having a woman donor (P = .0008) were associated with a greater risk of developing a second solid cancer. CONCLUSIONS: The authors concluded that patients undergoing allografting are at increased risk of developing a second solid cancer compared with the general population, particularly those of advanced age at the time of allograft. It is noteworthy that patients who had women as graft donors had an increased risk for developing a second solid cancer. This unexpected finding is a new observation and has not been reported previously. Extended follow-up will be needed to assess more fully the incidence and risk factors for the development of solid cancers, because the latency can be prolonged.

Adolescent↗

PubMed1996

Transfusion and stem cell support in cancer treatment.

Intensification of therapeutic regimens, improved patient survival, and advances in cytokine and cellular therapies have led to increasingly complex requirements for transfusion and stem cell support in cancer treatment. This article focuses on current and evolving issues in red blood cell, platelet, and granulocyte transfusion support, as well as measures to avoid increasingly important complications of transfusion therapy, such as alloimmunization, graft-versus-host disease, cytomegalovirus infection, and immunomodulation. Issues concerning current applications of hematopoietic stem cell transplantation and future prospects also are discussed.

Blood Transfusion↗

PubMedDate not supplied

Stem cell kinetics and intestinal cancer.

The conventional view that intestinal stem cells divide every few days so that each stem cell undergoes several thousand divisions in a lifetime is challenged. It is proposed that fully differentiated cells, even in old age, are no more than sixty divisions from the zygote. This concept leads to a model in which the intestinal crypts are maintained by a linear hierarchy of stem cells. The model is consistent with experimental data on the clonal origin of intestinal crypts and the observed crypt mutant frequency following exposure to chemical carcinogens. It also provides an explanation for an important paradox in cancer which is that cancer incidence rises rapidly with age but less rapidly with carcinogen dose even though both are thought to act through the same mechanism.

Aged↗