Proliferation Of Normal Tissue Research Articles

HAMARTOMATOUS TONGUE LESIONS IN PEDIATRIC PATIENTS: REPORT OF 8 CASES

A hamartoma is the proliferation of normal tissues that are considered endogenous to the site of occurrence. Hamartomas are rarely seen in the oral cavity. The aim of this study is to report clinicopathologic features of 8 additional tongue hamartoma cases in pediatric patients. Female patients outnumbered male patients by 1:6, and the age of patients ranged from 2 weeks to 4 years old. One case was associated with oral-facial-digital syndrome and another one with the presence of cleft palate and encephalocele. The most common histopathologic presentation was the presence of 4 concomitant components, including skeletal muscle, fat, salivary glands, nerves, and vessels. All cases were treated by surgical excision. Although hamartoma is rare, it must be including in differential diagnosis of masses located in tongues of pediatric patients.

Progress in the correlation between PTPN12 gene expression and human tumors.

Background:The global morbidity of cancer is rising rapidly. Despite advances in molecular biology, immunology, and cytotoxic and immune-anticancer therapies, cancer remains a major cause of death worldwide. Protein tyrosine phosphatase non-receptor type 12 (PTPN12) is a new member of the cytoplasmic protein tyrosine phosphatase family, isolated from a cDNA library of adult colon tissue. Thus far, no studies have reviewed the correlation between PTPN12 gene expression and human tumors.Methods:This article summarizes the latest domestic and international research developments on how the expression of PTPN12 relates to human tumors. The extensive search in Web of Science and PubMed with the keywords including PTPN12, tumor, renal cell carcinoma, proto-oncogenes, tumor suppressor genes was undertaken.Results:More and more studies have shown that a tumor is essentially a genetic disease, arising from a broken antagonistic function between proto-oncogenes and tumor suppressor genes. When their antagonistic effect is out of balance, it may cause uncontrolled growth of cells and lead to the occurrence of tumors. PTPN12 is a tumor suppressor gene, so inhibiting its activity will lead directly or indirectly to the occurrence of tumors.Conclusion:The etiology, prevention, and treatment of tumors have become the focus of research around the world. PTPN12 is a tumor suppressor gene. In the future, PTPN12 might serve as a novel molecular marker to benefit patients, and even the development of tumor suppressor gene activation agents can form a practical research direction.

Heparin treatment mitigates radiation-induced oral mucositis in mice by interplaying with repopulation processes

PurposeTo investigate the mechanistic background of the muco-protective effect of systemic heparin treatment on the development of radiation-induced oral mucositis in mice.Materials and methodsFractionated irradiation was given to the snouts of male C3H/Neu mice over 2 weeks (10 × 3 Gy), either alone or in combination with daily subcutaneous application of unfractionated or low molecular weight heparin (40 or 200 I.U./mouse, respectively). Over this course of 14 days, groups of mice (n = 3) were sacrificed every second day, their tongues excised and processed for histological analysis. The epithelial radiation response with and without heparin treatment was evaluated in terms of tissue morphology, proliferation and expression of cell contact molecules.ResultsSystemic treatment with heparins significantly reduced the cellular effects of irradiation to the oral epithelium. Heparin treated animals showed significantly higher total epithelial cell numbers and thickness throughout the study course. Bromodeoxyuridine (BrdU) incorporation analyses revealed that markedly more epithelial cells retained their proliferative capacity in the beginning of the first treatment week, but the proliferation of the mucosa was not stimulated during the rest of the study course. The expression of the adherens junction protein β‑catenin was slightly elevated in heparin treated animals, on day 2 the increase was statistically significant. The expression of e‑cadherin and occludin was mostly unaffected by the concomitant heparin treatment.ConclusionThe findings of this study indicate an interplay of additional heparin treatment with the repopulation processes, leading to an earlier onset of this adaptive radiation response in oral mucosa. Importantly, we could demonstrate that the protective potential of heparin did not rely on stimulation of normal tissue proliferation. Since both heparin preparations are already approved for clinical use, they are considered as promising candidates for future clinical studies.

Phosphorylated mTOR Expression Profiles in Human Normal and Carcinoma Tissues.

Mammalian target of rapamycin (mTOR) is a key controller of cell growth and proliferation in normal tissues and solid tumors. In the present study, an immunohistochemical analysis of the expression pattern of phosphorylated mTOR (p-mTOR) was performed in human normal fetal and adult tissues and various carcinoma tissues. p-mTOR expression showed tissue and cell type specificity in normal and cancer tissues. In normal fetal and adult tissues, p-mTOR staining was observed in the intestinal crypt, intrahepatic bile ductule, pancreatic duct, distal nephron of the kidney, umbrella cell of urothelium, mesothelial cell, and choroid plexus. In cancer tissues, p-mTOR expression was higher in adenocarcinoma than in other types of cancers, in metastatic cancer than in primary cancer, and in the forefront of the infiltrating cancer cells. These results suggest that p-mTOR is implicated not only in cell proliferation but also in tubular morphogenesis in normal and cancer tissues. In addition, mTOR activation appears to be associated with cancer cell invasion and migration in solid tumors.

Wnt9A Induction Linked to Suppression of Human Colorectal Cancer Cell Proliferation.

Most studies of Wnt signaling in malignant tissues have focused on the canonical Wnt pathway (CWP) due to its role in stimulating cellular proliferation. The role of the non-canonical Wnt pathway (NCWP) in tissues with dysregulated Wnt signaling is not fully understood. Understanding NCWP’s role is important since these opposing pathways act in concert to maintain homeostasis in healthy tissues. Our preliminary studies demonstrated that LiCl inhibited proliferation of primary cells derived from colorectal cancer (CRC). Since LiCl stimulates cell proliferation in normal tissues and NCWP suppresses it, the present study was designed to investigate the impact of NCWP components in LiCl-mediated effects. LiCl-mediated inhibition of CRC cell proliferation (p < 0.001) and increased apoptosis (p < 0.01) coincided with 23-fold increase (p < 0.025) in the expression of the NCWP ligand, Wnt9A. LiCl also suppressed β-catenin mRNA (p < 0.03), total β-catenin protein (p < 0.025) and the active form of β-catenin. LiCl-mediated inhibition of CRC cell proliferation was partially reversed by IWP-2, and Wnt9A antibody. Recombinant Wnt9A protein emulated LiCl effects by suppressing β-catenin protein (p < 0.001), inhibiting proliferation (p < 0.001) and increasing apoptosis (p < 0.03). This is the first study to demonstrate induction of a NCWP ligand, Wnt9A as part of a mechanism for LiCl-mediated suppression of CRC cell proliferation.

Chondroid Choristoma in the Border of Tongue: A Case Report

Choristoma is defined as a histologically normal tissue proliferation, which is not normally found in the anatomic site of proliferation. Chondroid choristoma of the oral soft tissue is a rare lesion, presenting cartilage where it is not expected. The patient was a 31-year-old white man presenting an endophytic firm mass on the right lateral border of the tongue also affecting the ventral surface that had appeared 5 years earlier, which was asymptomatic and measured approximately 3 cm in diameter. An incisional biopsy was performed with the hypothesis of pleomorphic adenoma. Histopathologic analysis confirmed the diagnosis of chondroid choristoma. The lesion was treated with its surgical enucleation, removing adjacent excess mucosae. The patient was followed up for 8 months with no recurrence.

151PD - Arid1A Role in Cell Cycle Regulation and Proliferation in Mouse and Human Gynaecological Tissues Reveals Potential Therapeutic Targets

ABSTRACT Aim: Ovarian clear cell carcinoma (OCCC) arises from endometriosis and can be considered an ectopic uterine cancer. ARID1A mutations occur as an early event in 50% of OCCC and 30% of high-grade endometrial cancers. We aimed to characterise the function of ARID1A in the normal uterus and ovary using an Arid1a mouse model and immortalised human ovarian surface epithelium cells. Methods: Arid1a expression during the mouse estrus cycle and its relationship to estrogen (ER), progesterone receptor and proliferation were assayed in a cohort of 28 mice. Illumina Beadchip arrays and MetaCore pathway analysis were used to assay ARID1A-driven transcriptional programmes in mouse uterus and, after siRNA-mediated knockdown, in mouse embryonic fibroblasts (MEF), immortalised human ovarian surface epithelium (IOSE) and JHOC-5 OCCC cells. SRB proliferation assays were performed in MEFs, IOSE and OCCC cell lines. Proliferation in the uterus was assessed 28 days after tamoxifen-induced knockout in Arid1afl/fl ROSA26Cre-ERT2 or wild type (WT) mice. Results: Arid1a expression was not hormonally regulated in the mouse uterus at either the mRNA or protein level, but Arid1a expression was correlated with stromal ER expression (r = 0.6, p = 0.0003). ARID1A-regulated genes in mouse uterus, MEFs and IOSE cells overlapped significantly (p = 1.7x10-13). Pathways involved in the G2/M checkpoint were significantly enriched in all 3 systems. The conserved core transcriptional program included AURKA, PLK1, PLK4, CCNB1 and CCND1. Conversely, genes involved in inflammation and cell adhesion pathways were ARID1A-regulated in JHOC-5 cells. ARID1A knockdown increased proliferation in MEFs, IOSE cells in an HNF1B-dependent manner and in 4 of 6 ARID1A-expressing OCCC cell lines. In vivo knockout in the uterine epithelium resulted in a dramatic increase in Ki67 staining in Arid1afl/fl compared to WT mice. Conclusions: A core ARID1A-driven transcriptional programme, conserved accross normal tissues and species appears to exist, centred around regulation of genes involved in the G2/M checkpoint. ARID1A loss promotes proliferation in normal tissues, providing important clues as to the mechanisms of ARID1A-driven carcinogenesis. Mitotic kinases emerge as potential therapeutic targets in ARID1A mutant tumours, an observation that is not evident from studies in cancer cell lines. Disclosure: All authors have declared no conflicts of interest.

Abstract IA11: Identification of therapeutic targets for MYC-driven cancers by functional genomics

Abstract The development of small molecules targeting MYC oncoproteins specifically in cancer cells has been a challenge, as MYC are DNA binding proteins required for proliferation of normal tissues. To circumvent these difficulties, we identified synthetic lethal interactions with MYC over-expression by high throughput siRNA screening (Toyoshima et al, 2012). Here, we will present validation of specific MYC-synthetic lethal genes (MYC-SL) in MYCN amplified neuroblastoma and ovarian cancer with high level of MYC using both RNAi approaches as well as small molecule inhibitors. To prioritize genes for future drug development, we carried out meta-analysis of genomic tumor data and obtained statistical significant associations between MYC alterations (i.e. gene amplification or overexpression) for selected MYC-SL genes. We also addressed the need of identifying biomarkers to stratify patients with solid tumors for activation of MYC and we will discuss the challenges and potential strategies, with particular focus on ovarian and breast cancers. Finally, to obtain a more global view of critical pathways that MYC-SL genes we performed network analysis of our targets. This analysis revealed that major points of vulnerabilities are linked to transcription and chromatin remodeling processes, DNA repair and cell-cycle checkpoints and metabolic functions. In addition, developmental, signaling and differentiation pathways represent unforeseen dependencies of MYC overexpressing cells. Altogether, these results provide a broad menu for therapeutic interventions to target MYC-driven cancers. *Current affiliation: Tohoku University School of Medicine, Sendai, Japan. Citation Format: Masafumi Toyoshima, In Sock Jang, Silvia Cermelli, Brady Bernard, Carla Grandori. Identification of therapeutic targets for MYC-driven cancers by functional genomics. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr IA11.

The prognostic significance of uncoupled proliferation and EGFR expression in oral cancer treated with surgery and radiation.

e21146 Background: Oral squamous cell cancer (OSCC) is characterized by poor prognosis, high morbidity and mortality. The epidermal growth factor receptor (EGFR) is overexpressed in most OSCCs; however, the association between EGFR and survival is inconsistent. Despite being linked to proliferation in normal tissue, few studies have examined the relationship between proliferation and EGFR expression, and OSCC outcomes. Methods: This retrospective study evaluated OSCC patients treated with surgery (n=17) or surgery and post-operative RT (n=47) between 1998-2005 at the Tom Baker Cancer Centre, Calgary, AB, Canada (median follow-up: 43 months). Tissue microarrays were assembled from pre-treatment formalin-fixed paraffin embedded tumor tissue. Clinico-pathologic data were obtained from chart review. EGFR and Ki67 expression were quantified using fluorescent IHC and AQUA technology. Regions of high and low EGFR expression were defined for each tumor core. We measured the ratio of Ki67 levels between high versus low EGFR expressing regions (Ki67EGFR-hi/Ki67EGFR-lo) to evaluate the relationship between proliferation and EGFR expression. Continuous variables were dichotomized using Xtile. Biomarker association with recurrence free survival (RFS) 5-year disease-specific survival (DSS) was analyzed using the Cox model. Results: In OSCC RFS and DSS associated with pathologic T-stage [RFS HR 2.8 (1.3-6.3), p=0.01; DSS HR 3.6 (1.5-8.4), p=0.004], and lymph node status [RFS HR 3.5 (1.6-7.7), p=0.002; DSS HR 6.4 (2.5-16.2), p<0.001]. Neither Ki67 nor EGFR alone significantly correlated with RFS or DSS. We observed a high Ki67EGFR-hi/Ki67EGFR-lo ratio in normal oral epithelium. In OSCC, a high Ki67EGFR-hi/Ki67EGFR-lo ratio (similar to normal epithelium) associated with improved survival [RFS HR 0.50 (0.23-1.08), p=0.076; DSS HR 0.46 (0.20-1.06), p=0.07]. The association with survival outcomes was more pronounced in patients who received RT [RFS HR 0.31 (0.12-0.83), p=0.02; DSS HR 0.40 (0.14-1.13), p=0.08]. Conclusions: Our results suggest that the uncoupling of proliferation and EGFR expression in OSCC represents a more aggressive and RT resistant tumor phenotype.

Angiomyolipomatous hamartoma of the upper lip: A rare case in an 8-month-old child and differential diagnosis

Hamartoma is a proliferation of normal tissues that are considered endogenous to the site of occurrence. In the head and neck region, hamartomas composed of other tissues different from blood and lymphatic vessels (hemangiomas and lymphangiomas) are very uncommon. We report an unusual case of upper lip angiomyolipomatous hamartoma in an 8-month-old patient. The patient underwent surgical treatment and the 1-year follow-up revealed no signs of recurrence. Angiomyolipomatous hamartoma is a very rare condition in the paediatric population group, especially in the head and neck region. It should be considered in the differential diagnosis of congenital lesions in childhood.

Expression of the telomeric retrotransposon HeT-A in Drosophila melanogaster is correlated with cell proliferation.

Drosophila melanogaster extends its telomeres by transposition of two non-LTR retrotransposons, HeT-A and TART, to chromosome ends. We have determined the tissue-specific expression of these two elements by whole-mount in situ hybridization with digoxigenin-labeled RNA sense and antisense probes in the germ line and in a variety of larval tissues during normal development in the wild type and in tissues of mutants that cause overproliferation. Our results indicate that transcript levels, which are a key component in the process of telomere elongation in D. melanogaster, are correlated with cell proliferation in normal tissues and that RNA levels are elevated in growth-stimulated tissues.

Expression of Geminin as a Marker of Cell Proliferation in Normal Tissues and Malignancies

Geminin interacts with a DNA replication initiation factor, Cdt1p, to suppress initiation of DNA replication in a Xenopus egg extract based cell-free system, leading to the expectation that the protein acts as an inhibitor of cell proliferation. Immunohistochemistry and immunoblotting for geminin, however, reveals that the protein is expressed specifically in proliferating lymphocytes and epithelial cells. This pattern is in contrast to the expression of a bona fide cell cycle inhibitor like p21/WAF1 that is specifically expressed in quiescent cells. Geminin is widely expressed in several malignancies and the number of geminin-expressing cells is directly proportional to the cell proliferation index as measured by Ki-67 expression. Therefore, instead of being a suppressor of cell proliferation, geminin expression is positively correlated with cell proliferation. Consistent with this observation, transient overexpression of wild-type geminin in cancer cells in culture did not produce a cell cycle block. A point mutation in the destruction box of geminin, however, results in a protein that is stabilized in G(1) and capable of arresting cells at the G(1)-S transition.

Chronotherapy of colorectal cancer

Chronotherapy consists of chemotherapy delivery according to circadian rhythms. These genetically based rhythms modulate cellular metabolism and cell proliferation in normal tissues. As a result, both the host tolerance and antitumor efficacy of 5-fluorouracil (5-FU) and oxaliplatin (l-OHP), like 30 other anticancer drugs, vary largely according to the dosing time in laboratory rodents. The transfer of this concept to the clinic is aimed primarily at increasing the dose-intensity of the therapy through adjustment of drug-delivery to 24h rhythms in host tolerance. A specific technology (programmable-in-time infusion pumps) enables administration of chronotherapy to fully ambulatory patients. Phase I–III clinical trials show chronotherapy significantly increases tolerance to high doses of cancer drugs and improves antitumor activity in patients with metastatic colorectal cancer. These safe conditions of drug-delivery led to the first demonstration of the high activity of the 5-FU–leucovorin–l-OHP protocol. Chronotherapy with these three drugs also allows surgical removal of previously unresectable liver and lung metastases. This novel medico-surgical management provides hope for the cure of metastatic disease in patients with unresectable colorectal cancer metastases.

Octreotide inhibits the secretion of interleukin-12 from mononuclear cells in human peripheral blood (PBMCs) in vitro.

The functional interactions between endocrine and immune systems play a relevant role in many basic physiological and pathological events such as cell proliferation and angiogenesis [1] [2]. Angiogenesis is a process of blood capillaries development during normal tissue proliferation (wound healing, embryogenesis) as well as during infection, ischemia, and cancer diseases. In vivo, several angiogenic modulators have been recognized in human and other species’ peptide molecules, such as vascular endothelial growth factor [2], interleukin-8 [3], and interleukin-12 [4]. Therefore, chemists have designed a lot of angiogenesis inhibitors, but only some of them are useful in clinical practice [5]. Octreotide (Sandostatin, SMS 201-995) is one of the somatostatin analogs and has been clinically useful in oncology, endocrinology and hematology for its strong inhibitory activity on multiple cell type proliferation and hormonal secretory processes [6]. Antiproliferative and antiangiogenic properties of somatostatin or octreotide are a result of binding with specific receptors. The five subtypes of somatostatin receptors have been discovered (SRRT 1-5) and described [6] [7]. The presence of somatostatin receptors on immune cells (monocytes and lymphocytes) indicates that octreotide (OCT) may be one of the regulators of the immune cell function in humans [3] [8]. However, there is no data in literature about the effect of OCT on interleukin-12 (IL-12) secretion from immune cells in human peripheral blood.

The Denekamp Diadems&A Review of Julie's Achievements

Dr Julie Denekamp, DSc, PhD, BSc was present at a symposium held in her honour in Uppsala in February 2001. This article presents some biographical details and summarizes the main features of the scientific work for which she is known in radiobiology applied to cancer treatment, now called Translational Research. Topics include fractionation, proliferation in normal tissues as well as tumours, early versus late reactions, radiosensitizers, vascular attack in tumours, neutrons (and pions), radiosensitizers, radioprotectors, hyperthermia, research methodology, and theoretical modelling.

Human DNA topoisomerase II-alpha: A new marker of cell proliferation in invasive breast cancer

DNA topoisomerase II-alpha is the molecular target of doxorubicin, an active drug used in the therapy of breast cancer. From many in vitro studies, it is known that high levels of topo II-alpha expression correlate with drug sensitivity, and low levels of topo 11-alpha correlate with drug resistance. In addition, the enzyme is known to be a marker of cell proliferation in normal tissues. Because the number of proliferating cells in a breast cancer has been shown to be prognostically important, and because doxorubicin is used in the treatment of breast cancer, we hypothesized that the measurement of topo 11-alpha in breast cancer may not only give drug sensitivity information but also may yield important data on cell proliferation. In this study, formalin-fixed, paraffin-embedded tissue from 30 specimens of invasive breast cancer from 20 patients were immunohistochemically stained for topo II-alpha with a mouse monoclonal antibody. For each case, a topo II-alpha index was determined that represents the number of positive-staining tumor cells divided by the total number of tumor cells counted times 100. A similar index was determined for MIB1, a known cell proliferation marker. Each case was also graded according to the modified Bloom-Richardson criteria and evaluated for c- erbB-2 amplification, hormonal status, S-phase fraction, and mitotic index. The topo II-alpha index correlates better with the MIB1 index than with the S-phase fraction or mitotic index. The topo II-alpha expression in breast cancer ranges from low (topo II-alpha index <1) to high (topo II-alpha index = 86). Amplification of cerbB-2 was observed in 4 of 28 cases (14%) but did not correlate with high topo 11-alpha indices. We conclude that measurement of topo II-alpha in invasive breast cancer can be readily performed by immunohistochemical staining, and it gives information on the number of cycling tumor cells. In addition, because the enzyme is the molecular target of doxorubicin, the expression of the enzyme may relate also to the sensitivity or resistance of the tumor to doxorubicin-based chemotherapeutic protocols.

Comparative studies between freshly isolated and spontaneously immortalized bovine granulosa cells: Protein secretion, steroid metabolism, and responsiveness to growth factors

A bovine granulosa cell line (BGC-1) has been obtained by spontaneous immortalization of primary cultures. BGC-1 cells have retained some characteristics of primary cultures, such as the hormonal regulation of fibronectin biosynthesis. In the present study we have compared BGC-1 cells and primary cultures of bovine granulosa cells in terms of protein secretion, steroid metabolism, and mitogenic responses to growth factors. The pattern of protein secretion in BGC-1 cells was qualitatively similar to that of primary cultures. The main differences were a higher proportion of fibronectin and the relative amounts of several other unidentified proteins. Progesterone levels in BGC-1 cultures were undetectable. When BGC-1 cells and primary cultures were incubated with [3H]-pregnenolone, the former showed a lower conversion rate to progesterone. In contrast, the conversion rate of [3H]-progesterone to 5 alpha-reduced metabolites was markedly increased in BGC-1 cells. We also examined the effects of epidermal growth factor (EGF), insulin like growth factor-I (IGF-I), and transforming growth factor-beta (TGF-beta) on DNA synthesis under serum-free conditions. Both primary cultures and BGC-1 cells exhibited a stimulatory response to EGF and IGF-I on [3H]-thymidine incorporation. Neither BGC-1 cells nor primary cultures showed a significant response to TGF-beta when added alone. However, in the presence of a combination of EGF and IGF-I, TGF-beta displayed an inhibitory effect on primary cultures while it stimulated DNA synthesis in BGC-1 cells even further. The addition of conditioned medium from BGC-1 cells (BGC-1-CM) stimulated DNA synthesis on primary cultures to a greater extent than the addition of conditioned medium from primary cultures. These results suggest that BGC-1 cells may be a useful model to study the regulation of granulosa cell function during the period previous to the preovulatory stage of follicular development. The differential responses of the immortalized cells to growth regulators may offer some clues on the mechanisms that control cell proliferation in normal tissues.

Repopulation in human tumors. A biological background for fractionation in radiotherapy.

Tumor repopulation plays a major role in the response of tumors to radiotherapy or chemotherapy but its degree varies widely among human tumors. Its mechanism has not been elucidated, however it is unlikely that repopulation can be simply explained by the greater availability of oxygen and nutrients resulting from the reduction in tumor mass. In normal tissues, such as bone marrow, treated cells release stimulating factors which are able to recruit quiescent cells into proliferation. Similar mechanisms have been observed in experimental tumors and their existence is probable in human tumors. A low pretreatment proliferation index and low cell density indicate that the control mechanisms which regulate cell proliferation in normal tissues are still partially operating in these tumors. In such tumors an increase in the level of cell proliferation during or after treatment has often, but not always, been observed. There is not yet a clear guide for predicting tumor proliferation rate under treatment and further investigations are needed.

Comparison of the circadian variation in cell proliferation in normal and neoplastic colonic epithelial cells

Circadian variations in cell proliferation in normal tissues have been recognised for many years but comparable phenomena in neoplastic tissues appear not to have been reported. Adenomas and carcinomas were induced in mouse colon by injection of dimethylhydrazine (DMH) and cell proliferation in these tumors was measured stathmokinetically. In normal intestine cell proliferation is fastest at night whereas in both adenomas and carcinomas it was found to be slower at night than in the middle of the day. Chemical sympathectomy was found to abolish the circadian variation in tumor cell proliferation.

L.H. Gray medal lecture: Cell kinetics and radiation oncology

Development of the study of human tumor cell kinetics during the past decades has deepened our understanding of the natural history of human cancers. Mathematical models based on the data which have been accumulated may help to evaluate, for the various types of human tumors, the time during their growth that the dissemination process occurred and to calculate the size distribution of the subclinical metastases at the time of treatment of the primary tumor. The perturbations caused.by radiotherapy and chemotherapy are complex and include reassortment of surviving cells and repopulation. Currently it appears difficult in clinical practice to take advantage of cell reassortment while the differences in the rate and in the duration of repopulation between normal and neoplastic tissues are exploited in most therapeutic regimens. A better knowledge of cell and tissue kinetics following treatment may help to optimize the treatment scheduling in particular during combined administration of radiotherapy and chemotherapy. The study of the kinetics of proliferation in normal tissue has shown the existence of several types of inhibitory and stimulatory humoral factors. These, when purified, can be used to manipulate the proliferation of critical normal tissues in order to protect them during the administration of cell cycle specific drug or to accelerate their regeneration after treatment.