multistep process of cancer
103467874
A multistep process of cancer associated fibroblasts determination under CSL p53 control
Stromal fibroblast senescence has been linked to the aging associated increase of tumors. However, in epithelial cancer, density and proliferation of cancer associated fibroblasts (CAF) are frequently increased, rather than decreased. We previously showed that genetic deletion or down modulation of the canonical Notch effector CSL/RBP JK in dermal fibroblasts is sufficient for CAF activation with consequent development of keratinocyte derived tumors. We show here that CSL silencing induces senescence of primary fibroblasts from dermis, oral mucosa, breast and lung. CSL functions in these cells as direct repressor of multiple senescence and CAF effector genes. It also physically interacts with p53, repressing its activity. CSL is down modulated in stromal fibroblasts of premalignant skin actinic keratosis lesions and squamous cell carcinomas (SCC) while p53 gene expression and function is down modulated only in the latter, with paracrine influences of incipient cancer cells as a likely culprit. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances CAF effector gene expression and promotes stromal and cancer cell expansion. The findings support a CAF activation/stromal co evolution model under convergent CSL/p53 control of likely clinical relevance.
Maria-Giuseppina Procopio
206528863
Cellular Pliancy and the Multistep Process of Tumorigenesis.
Completion of early stages of tumorigenesis relies on the dynamic interplay between the initiating oncogenic event and the cellular context. Here, we review recent findings indicating that each differentiation stage within a defined cellular lineage is associated with a unique susceptibility to malignant transformation when subjected to a specific oncogenic insult. This emerging notion, named cellular pliancy, provides a rationale for the short delay in the development of pediatric cancers of prenatal origin. It also highlights the critical role of cellular reprogramming in early steps of malignant transformation of adult differentiated cells and its impact on the natural history of tumorigenesis.
Cancer cell
Alain Puisieux Roxane M Pommier Anne Pierre Morel Fabrice Lavial
9086690
Mechanisms of cancer cell metastasis to the bone: a multistep process.
For metastasis to occur, tumor cells must first detach from their tissue of origin. This requires altering both the tissue of origin and the cancer cell. Once detached, cancer cells in circulation must also acquire survival mechanisms. Although many may successfully disseminate, variation exists in the efficiency with which circulating tumor cells home to and invade the bone marrow as metastastic seeds. Disseminated tumor cells that do successfully invade the marrow are secured by cell cell and cell extracellular matrix adhesion. However, establishing a foothold in the marrow is not sufficient for disseminated tumor cells to create metastases. A significant latent phase must be overcome by either rescuing cellular proliferation or attenuating micrometastatic mass dormancy programs. Finally, growing metastases fuel osteolysis, osteoblastogenesis and T cell differentiation, creating a variety of tumor phenotypes. Each step in the metastatic cascade is rich in biological targets and mechanistic pathways.
Future oncology
Lalit R Patel Daniel F Camacho Yusuke Shiozawa Kenneth J Pienta Russell S Taichman
5740352
Enzyme Instructed Self Assembly: A Multistep Process for Potential Cancer Therapy
The central dogma of the action of current anticancer drugs is that the drug tightly binds to its molecular target for inhibition. The reliance on tight ligand receptor binding, however, is also the major root of drug resistance in cancer therapy. In this article, we highlight enzyme instructed self assembly (EISA) the integration of enzymatic transformation and molecular self assembly as a multistep process for the development of cancer therapy. Using apoptosis as an example, we illustrate that the combination of enzymatic transformation and self assembly, in fact, is an inherent feature of apoptosis. After the introduction of EISA of small molecules in the context of supramolecular hydrogelation, we describe several key studies to underscore the promises of EISA for developing cancer therapy. Particularly, we will highlight that EISA allows one to develop approaches to target "undruggable" targets or "untargetable" features of cancer cells and provides the opportunity for simultaneously interacting with multiple targets. We envision that EISA, used separately or in combination with current anticancer therapeutics, will ultimately lead to a paradigm shift for developing anticancer medicine that inhibit multiple hallmark capabilities of cancer.
Bioconjugate chemistry
Jie Zhou Bing Xu
1238174
CD24 is a new oncogene, early at the multistep process of colorectal cancer carcinogenesis.
BACKGROUND AIMS The aim of this study was to identify genes that play a role in colorectal cancer (CRC) carcinogenesis by analysis of differential gene expression of normal and transformed CRC cell lines. METHODS Gene expression array analysis [RG U34] GeneChip) was performed in normal and transformed rat intestinal epithelial cells before and after exposures to celecoxib. In particular, we were looking for (1) altered gene expression in the transformed cells that reverts to normal following exposure to a selective cyclooxygenase 2 inhibitor, (2) novel genes, and (3) genes encoding membrane receptors or ligands. As a validation of the results and for human patients, immunohistochemistry was performed on 398 biological samples from the gastrointestinal tract (normal, polyps, and adenocarcinomas) Human cancer cell lines were tested for their response to anti CD24 monoclonal antibodies. RESULTS A total of 1081 genes were differently expressed following malignant transformation; 71 genes showed altered expression that reverted to normal following treatment with celecoxib, including the CD24 gene. Immunohistochemistry confirmed that increased expression of CD24 is an early event in CRC carcinogenesis. It was expressed in 90.7% of adenomas and 86.3% of CRCs. Very low expression was seen in normal epithelium (16.6% Human cancer cell lines showed growth inhibition in response to the antibodies, according to their expression levels of CD24 and in dose and time dependent manners. These results were repetitive for 3 different antibodies. CONCLUSIONS CD24 is overexpressed in the colonic mucosa, already at an early stage of carcinogenesis. It may be a useful target for early detection and in CRC therapy.
Gastroenterology
Eyal Sagiv Lorenzo Memeo Adi Karin Diana Kazanov Jasmine Jacob-Hirsch Mahesh M Mansukhani Gidi Rechavi Hanina Hibshoosh Nadir Arber
212615332
The biological implications of Yin Yang 1 in the hallmarks of cancer
Tumorigenesis is a multistep process characterized by the acquisition of genetic and epigenetic alterations. During the course of malignancy development, tumor cells acquire several features that allow them to survive and adapt to the stress related conditions of the tumor microenvironment. These properties, which are known as hallmarks of cancer, include uncontrolled cell proliferation, metabolic reprogramming, tumor angiogenesis, metastasis, and immune system evasion. Zinc finger protein Yin Yang 1 (YY1) regulates numerous genes involved in cell death, cell cycle, cellular metabolism, and inflammatory response. YY1 is highly expressed in many cancers, whereby it is associated with cell proliferation, survival, and metabolic reprogramming. Furthermore, recent studies also have demonstrated the important role of YY1 related non coding RNAs in acquiring cancer specific characteristics. Therefore, these YY1 related non coding RNAs are also crucial for YY1 mediated tumorigenesis. Herein, we summarize recent progress with respect to YY1 and its biological implications in the context of hallmarks of cancer.
Theranostics
Ian Timothy Sembiring Meliala Rendy Hosea Vivi Kasim Shourong Wu
85736423
Coordinating Wnt/LRP6/Axin/Snail Axis on Multistep Process of Uterine Cervical Cancer(Short title Wnt/LRP6/Axin/Snail axis in Cancer)
A15 Wnt signaling is involved in the normal development and tumorigenesis via epithelial mesenchymal transition (EMT) initiated by down regulation of E cadherin by the transcription factor Snail. Wnt signaling inhibits Snail phosphorylation through Axin2 dependent pathway that sustains nuclear accumulation of Snail by driving GSK3b nucleocytoplasmic export, then consequently increases Snail protein levels and induces an EMT. However, the roles of Wnt and Axin expression and their functional implication on Snail dependent EMT program are not clear during the multistep carcinogenic process. We examined that canonical Wnt signaling engaging multistep carcinogenic process of uterine cervical cancer through Wnt Axin2 Snail axis. In normal cervical mucosa, Wnt1, Wnt3a, and Axin2 mRNA expression were localized in basal cell layer suggesting that canonical Wnt is required for maintenance of self renewal program of cervical epithelial cells. With progression to cervical intraepithelial neoplasia (CIN) and carcinoma, Wnt1, Wnt3a, Axin2, and Snail expression were gradually increased in patient samples suggesting that canonical Wnt pathway is involved in early step of carcinogenesis in uterine cervix. LRP6 and Axin2 transfected cells showed the highly increased nuclear Snail resulted from decreased level of nuclear GSK3b, indicating that LRP6 Axin2 serves to stabilize Snail protein levels and sustains its nuclear accumulation by driving GSK3b. RNA interference of Axin2 and Snail on SiHa cells relieved E cadherin proximal promoter activity and block the in vivo chorioalantoic membrane invasion. These results suggest the canonical Wnt signaling regulating Axin2 GSK3b compartmentalization may important for stabilization of E cadherin repressor Snail during the multistep carcinogenic process of uterine cervix. It may lead to not only tracing the proper biomarker of cancer progression, but also the development of new targets for therapeutic intervention in cancer.
Hyun Sil Kim Ju Kyoung Ryu So Young Cha Nam Hee Kim Sang Hwy Lee Yoon Jung Choi Jong In Yook
208283966
Preclinical imaging of the cellular and molecular events in the multistep process of bone metastasis.
Bone metastasis is a complex process that ultimately leads to devastating metastatic bone disease. It is therefore of key interest to unravel the mechanisms underlying the multistep process of skeletal metastasis and cancer induced bone disease, and to develop better treatment and management of patients with this devastating disease. Fortunately, novel technologies are rapidly emerging that allow real time imaging of molecules, pathogenic processes, drug delivery and drug response in preclinical in vivo models. The outcome of these experimental studies will facilitate clinical cancer research by improving the detection of cancer cell invasion, metastasis and therapy response.
Geertje van der Horst Gabri van der Pluijm
16535275
JC virus in the pathogenesis of colorectal cancer, an etiological agent or another component in a multistep process?
JCV infection occurs early in childhood and last throughout life. JCV has been associated to colorectal cancer and might contribute to the cancer phenotype by several mechanisms. Among JCV proteins, particularly two of them, large T antigen and agnoprotein, can interfere with cell cycle control and genomic instability mechanisms, but other viral proteins might also contribute to the process. Part of viral DNA sequences are detected in carcinoma lesions, but less frequently in adenomas, and not in the normal surrounding tissue, suggesting they are integrated in the host cell genome and these integrations have been selected; in addition viral integration can cause a gene, or chromosomal damage. The inflammatory infiltration caused by a local chronic viral infection in the intestine can contribute to the selection and expansion of a tumor prone cell in a cytokine rich microenvironment. JCV may not be the cause of colorectal cancer, but it can be a relevant risk factor and able to facilitate progression at one or several stages in tumor progression. JCV transient effects might lead to selective expansion of tumor cells. Since there is not a direct cause and effect relationship, JCV infection may be an alternative to low frequency cancer predisposition genes.
Virology Journal
Tatiana Rasteiro Coelho Luis Pereira de Almeida Pedro A Lazo
73453480
Perineural invasion of cancer: a complex crosstalk between cells and molecules in the perineural niche.
Perineural invasion (PNI) can be found in a variety of malignant tumors. It is a sign of tumor metastasis and invasion and portends the poor prognosis of patients. The pathological description and clinical significance of PNI are clearly understood, but exploration of the underlying molecular mechanism is ongoing. It was previously thought that the low resistance channel in the anatomic region led to the occurrence of PNI. However, with rapid development of precision medicine and molecular biology, we have gradually realized that the occurrence of PNI is not the result of a single factor. The latest study suggests that PNI of cancer is a continuous and multistep process. A specific peripheral microenvironment, also called the perineural niche, is formed by neural cells, supporting cells, recruited inflammatory cells, altered extracellular matrix, blood vessels, and immune components in the background of carcinoma. Various soluble signaling molecules and their receptors comprise a complex signal network, which achieves the interaction between nerve and tumor. Nerve cells and tumor cells can interact directly or through the opening and closing of the signal transduction pathways and/or the recognition and response of the ligands and receptors. The information is transferred to the targets accurately and effectively, leading to the specific interactions between the nerve cells and the malignant tumor cells. PNI occurs through changes in nerve cells and supporting cells in the background of cancer; change and migration of the perineural matrix; enhancement of the viability, mobility, and invasiveness of the tumor cells; injury and regeneration of nerve cells; interaction, chemotactic movement, contact, and adherence of the nerve cells and the tumor cells; escape from autophagy, apoptosis, and immunological surveillance of tumor cells; and so on. Certainly, exploring the mechanism of PNI clearly has great significance for blocking tumor progression and improving patient survival. The current review aims to elucidate the cellular and molecular mechanisms of PNI, which may help us find a strategy for improving the prognosis of malignant tumors.
American journal of cancer research
Shuhai Chen Bingyuan Zhang Bin Zhou Cheng-zhan Zhu Leqi Sun Yu-jie Feng