Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion. Intratumoral hypoxia and genetic alterations can lead to HIF-1alpha overexpression, which has been associated with increased patient mortality in several cancer types. In preclinical studies, inhibition of HIF-1 activity has marked effects on tumour growth. Efforts are underway to identify inhibitors of HIF-1 and to test their efficacy as anticancer therapeutics.

Targeting HIF-1 for cancer therapy

Researchers have been studying metastasis for more than 100 years, and only recently have we gained insight into the mechanisms by which metastatic cells arise from primary tumours and the reasons that certain tumour types tend to metastasize to specific organs. Stephen Paget's 1889 proposal that metastasis depends on cross-talk between selected cancer cells (the 'seeds') and specific organ microenvironments (the 'soil') still holds forth today. It is now known that the potential of a tumour cell to metastasize depends on its interactions with the homeostatic factors that promote tumour-cell growth, survival, angiogenesis, invasion and metastasis. How has this field developed over the past century, and what major breakthroughs are most likely to lead to effective therapeutic approaches?

https://www.nature.com/articles/nrc1098.pdf?proof=t

The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited

Cancer Metastasis: Building a Framework

The contribution of tumorigenic stem cells to haematopoietic cancers has been established for some time, and cells possessing stem-cell properties have been described in several solid tumours. Although chemotherapy kills most cells in a tumour, it is believed to leave tumour stem cells behind, which might be an important mechanism of resistance. For example, the ATP-binding cassette (ABC) drug transporters have been shown to protect cancer stem cells from chemotherapeutic agents. Gaining a better insight into the mechanisms of stem-cell resistance to chemotherapy might therefore lead to new therapeutic targets and better anticancer strategies.

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Tumour stem cells and drug resistance

Tumor Metastasis: Molecular Insights and Evolving Paradigms

2346 Heat shock proteins (hsps) are molecular chaperones which synthesized by cells in response to various stress conditions and associated with tumor neogenesis or carcinogenesis and the biological behaviour of tumors. The expression of hsps in neoplasia has been implicated in the regulation of apoptosis. Recently hsps were emerged to be a novel molecular target in anticancer protocol. The objective of this study was to investigate to clarify the significance of hsp90/70 in breast cancer and effect of geldanamycin (blocker of hsp90) and quercetin (blocker of hsp70) on growth inhibition in different breast cancer cell lines. First, expression levels of hsp 90/70 were studied by immunohistochemistry on tissue sections from 61 invasive ductal carcinoma of breast including 11 ductal carcinoma in situ and 26 normal breast tissues including 12 fibrocystic changes as control. Hsp 70/90 expression were evaluated via grading systems which are percentage-grade is classified by 0(negative),1(25%>),2(25%

The role of heat shock protein 90/70 as potential molecular therapeutic targets in breast cancer

A human cancer cell line was found to be heterogeneous for expression of the epidermal growth factor receptor (EGFR). Clones and variants of this cell line were separated on the basis of EGFR expression level, and those expressing high EGFR had different growth characteristics, in vitro and in vivo, than variants expressing low levels of EGFR. Karyotype analysis revealed that the heterogeneity was the result of mixing of two lines, the 2774 ovarian cancer cell line, and the SW620 colon cancer cell line. Our results reinforce the necessity for accurate identification of cell lines. Also, that measurement of gene expression on a single cell level, for example by flow cytometric analysis, can be more informative than measurements of cell lysates, since the initial indication of 'heterogeneity' would not have been detected by northern or western blotting. The different cell types retained characteristic growth patterns when injected i.p. in nude mice, i.e. peritoneal carcinomatosis and ascites formation by the 2774 ovarian cancer cells, and liver metastasis and growth of discrete abdominal tumors by the SW620 colon cancer.

Distinctive karyotypes and growth patterns in nude mice reveal cross-contamination in an established human cancer cell line.

Metastatic disease, notably to the lungs, liver, bone, and brain, is the most common cause of death from breast cancer, despite advances in surgical and clinical management. Two basic principles govern the process of metastasis: first, that tumors are heterogeneous populations of cells; and second, that the process of metastasis is a sequence of events that depends on tumor cell properties and interactions with the microenvironment at the sites of metastasis. In theory, inhibitors targeted at any of the steps of metastasis have the potential to inhibit metastatic progression. In vitro assays cannot simulate accurately the complex process of metastasis, and the use of appropriate animal models is necessary to model the process, and for testing the impact of targeted inhibitors on the growth and development of breast cancer metastasis. Animal models of the growth and metastasis of rodent and human breast cancer cells have been developed, including models that target the metastatic growth in key organs sites such as the bone and brain.

Clinically relevant metastatic breast cancer models to study chemosensitivity.

Skin cancers induced in mice by UV radiation often exhibit a regressor phenotype. In order to determine how tumors escape the immune defenses of the normal immunocompetent host, we sought to isolate progressor variants from a UV radiation-induced C3H mouse regressor fibrosarcoma cell line, UV-2240, by transfection with an activated Ha-ras oncogene. A cotransfection protocol using pSV2-neo DNA, which confers resistance to the antibiotic G418, was used to select transfected cells. Injection of Ha-ras-transfected UV-2240 cells s.c. into immunocompetent C3H mice produced tumors in four of 36 animals. In contrast, UV-2240 cells transfected with pSV2-neo DNA alone or mock transfected with CaPO4 did not produce tumors in normal C3H mice. DNAs from cell lines established from Ha-ras-induced tumors contained unique Ha-ras sequences in addition to those sequences endogenous to UV-2240 cells. However, the Ha-ras-induced progressor variants did not overexpress the Mr 21,000 protein. The Ha-ra-induced progressor variants produced experimental lung metastasis in both normal C3H and nude mice, although they induced more lung nodules in nude mice than in normal C3H mice. In addition, all four Ha-ras-induced progressor variants produced significantly more experimental lung metastases in nude mice than did the parent UV-2240 cell line. However, both the parental UV-2240 cell line and the Ha-ras-induced progressor variants expressed similar levels of H-2Kk and H-2Dk antigens and were immunologically cross-reactive, as determined by in vitro cytotoxic T-lymphocyte and in vivo immunization-challenge assays. These results indicate that the progressor phenotype of the Ha-ras-induced tumor variants is not due to loss of tumor-specific transplantation or Class I major histocompatibility complex antigens. This implies that some tumor cells can escape the immune defenses of the normal immunocompetent host by mechanisms other than loss of tumor-specific transplantation and Class I major histocompatibility antigens.

https://cancerres.aacrjournals.org/content/canres/50/11/3159.full.pdf

Immune response to progressor variants derived from transfection of an ultraviolet radiation-induced C3H mouse regressor tumor cell line with activated Harvey-ras oncogene.

K1735 murine melanoma cells transfected with p53 cDNAs bearing specific point mutations are metastatic in nude mice, whereas the parent and control-transfected cells are nonmetastatic. To determine whether p53 gene mutations regulate genes associated with angiogenesis, growth, and metastasis, we examined expression of vascular endothelial growth factor I, IGF-I receptor, epidermal growth factor insulin-like growth factor I, IGF-I receptor, epidermal growth factor receptor, c-MET, and thrombospondin 1 in K1735 cells transfected with one of four different mutant p53 cDNAs. Northern blot analysis demonstrated differential upregulation of these genes in cells transfected with different mutant p53 cDNAs. Up-regulation of angiogenesis-, growth-, and metastasis-related genes by mutant p53 may contribute to metastasis formation.

Janet E. Price

Papers

The role of heat shock protein 90/70 as potential molecular therapeutic targets in breast cancer

Distinctive karyotypes and growth patterns in nude mice reveal cross-contamination in an established human cancer cell line.

Clinically relevant metastatic breast cancer models to study chemosensitivity.

Immune response to progressor variants derived from transfection of an ultraviolet radiation-induced C3H mouse regressor tumor cell line with activated Harvey-ras oncogene.

Regulation of genes associated with angiogenesis, growth, and metastasis by specific p53 point mutations in a murine melanoma cell line.