EDITORIALS

Promiscuous Transcription of Vascular Endothelial Growth Factor and Survival of Tumors

Lee M. Ellis, Gary E. Gallick

Affiliations of authors: L. M. Ellis (Departments of Surgical Oncology and Cancer Biology), G. E. Gallick (Department of Cancer Biology), The University of Texas M.D. Anderson Cancer Center, Houston.

Correspondence to: Lee M. Ellis, M.D., Department of Surgical Oncology, Box 106, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 (e-mail: lellis{at}mdanderson.org).

Angiogenesis, the process of formation of new blood vessels, is among the most active areas of research, not only in the field of cancer but also in the fields of developmental biology, cardiovascular disease, diabetes, and rheumatology. Until recently, there has been a great divide between the expansion of knowledge obtained by basic science investigations and clinical application. By necessity, various factors, including economic forces and patient advocacy, have provoked investigators to become increasingly aware of the need to interpret basic science findings in light of potential clinical applications.

In this issue of the Journal, Sheta et al. (1) have demonstrated that cell–cell communication between human prostate cancer cells leads to increased transcription of vascular endothelial growth factor (VEGF), the most potent angiogenic factor recognized to date. In contrast, normal prostate epithelium grown to confluence does not express higher levels of VEGF. Cell–cell contact is clearly required, since soluble factors secreted from prostate cancer cells or the binding of these cells to extracellular matrix components does not increase VEGF transcription. In elegant studies, Sheta et al. demonstrate that cell–cell contact induces a signaling pathway mediated by Src, focal adhesion kinase (FAK), and phosphatidylinositol 3-kinase (PI3K), leading to the activation of mitogen-activated protein kinase (MAPK) in a Ras-independent manner.

What are the implications of these findings, and are they potentially important in the clinic? The ability of tumor cells to escape density-dependent growth inhibition is one of their in vitro hallmarks. However, little work has succeeded in elucidating signaling pathways responsible for lack of contact inhibition or if this property is truly important to tumor growth in vivo. The demonstration by Sheta et al. (1) that contact of tumor cells leads directly to increased transcription of VEGF not only provides strong evidence for the potential relevance of cell–cell contact but also furthers our understanding of the possible mechanisms of tumor progression. Thus, these studies provide the first insights into potential targets for drug development that may lead to partial restoration of contact inhibition.

As VEGF has become recognized as a dominant regulatory factor in tumor angiogenesis, we have also come to recognize that a multitude of factors regulate its expression. These factors include small peptides (such as insulin-like growth factor, epidermal growth factor, interleukin 1, and platelet-derived growth factor), acidity, and, most importantly, hypoxia (26). In addition, aberrant intracellular signaling resulting from activated Ras, Raf, or Src can lead to VEGF induction (79). Furthermore, inactivation of tumor suppressor genes, such as p53 and VHL, reverses repression of VEGF expression (1014).

Sheta et al. (1) demonstrate that cell density increases VEGF expression through an FAK–PI3K–MEK (i.e., MAPK/extracellularregulated kinase) pathway. While some signaling molecules (e.g., erk) are shared by other pathways indicated above, the Ras independence of prostate tumor cell–cell contact-mediated VEGF expression places this pathway in common only with integrin-mediated signaling pathways regulating cellular motility [reviewed in (15)]. Thus, both mitogenic and motogenic (i.e., motility) pathways lead to VEGF expression.

These findings demonstrate several important principles. Important processes in biology are likely to have evolved, such that their activation is mediated by multiple pathways. Furthermore, although for teaching purposes and for modeling, we often draw pathways as distinct (i.e., the "mitogenic" pathway, the "stress-activated" pathway, etc.), it is critical to appreciate the tremendous amount of cross-talk among these pathways. The study by Sheta et al. (1) dissects out the cross-talk in VEGF induction by cell–cell contact. It also points out another very critical issue. Directing therapy to reduce expression of an important factor must take into account the probability that multiple pathways lead to its induction. For example, since activated ras is known to induce VEGF, one might naively surmise that inhibition of ras function will substantially lower VEGF expression and, hence, inhibit angiogenesis.

However, numerous studies, including the study by Sheta et al. (1), demonstrate that inhibition of a specific signal transduction pathway will not be sufficient to inhibit angiogenesis. In addition, effective inhibition of a particular angiogenic pathway may lead to selection of cells whose angiogenic activity is mediated through alternative pathways. Tumor cells evolve to survive under adverse conditions, such as hypoxia, acidity, and even chemotherapy or radiotherapy. Thus, these robust cells are able to maintain their nutrient blood supply by utilizing redundant pathways to induce expression of angiogenic factors (as well as other factors that may mediate proliferation, survival, etc.). In solid tumors, it is likely that agents that target a single pathway or factor will not effectively lead to sustained tumor regression or even stabilization. The data presented by Sheta et al. provide more evidence that the signaling pathways that mediate tumor progression are far more complex than once believed. Although the idea that inhibiting multiple signaling pathways may be the best method for inhibiting the processes that lead to tumor growth and metastasis, we are again faced with the prospect that this strategy may also lead to toxicity to the host. One must always remember that signaling pathways first evolved to regulate normal physiologic processes, and the aberrant activity of these pathways is what leads to pathology.

When Dr. Judah Folkman began to elucidate the field of tumor angiogenesis approximately 30 years ago, his ideas were met with a great deal of skepticism. Over the last 10 years, this skepticism has changed to a great deal of promise, leading to the belief that we may be able to alter angiogenesis to suit the needs of patients, i.e., to increase angiogenesis in those patients with occlusive vascular disease and to decrease angiogenesis in those patients with tumors. Although the concepts seem relatively simple, practically speaking, the biology is incredibly complex.

We are just beginning to understand the complexities of the factors that regulate angiogenesis, both external to the cell and within the intracellular signaling pathways. More insightful research, such as that reported in this issue of the Journal, is essential to reaping clinical benefit from knowledge in this field.

NOTES

Supported in part by the Gillsohn Longenbaugh Foundation (L. M. Ellis and G. E. Gallick) and by Public Health Service grants CA74821 (L. M. Ellis) and CA65527 (G. E. Gallick) from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.

REFERENCES

1 Sheta EA, Harding MA, Conaway MR, Theodorescu D. Focal adhesion kinase, Rap1, and transcriptional induction of vascular endothelial growth factor. J Natl Cancer Inst 2000;92:1065–73.[Abstract/Free Full Text]

2 Valter MM, Wiestler OD, Pietsche T. Differential control of VEGF synthesis and secretion in human glioma cells by IL-1 and EGF. Int J Dev Neurosci 1999;17:565–77.[Medline]

3 Tsai JC, Goldman CK, Gillespie GY. Vascular endothelial growth factor in human glioma cell lines: induced secretion by EGF, PDGF-BB, and bFGF. J Neurosurg 1995;82:864–73.[Medline]

4 Akagi Y, Liu W, Zebrowski B, Xie K, Ellis LM. Regulation of vascular endothelial growth factor expression in human colon cancer by insulin-like growth factor-I. Cancer Res 1998;58:4008–14.[Abstract]

5 Akagi Y, Liu W, Xie K, Zebrowski B, Shaheen RM, Ellis LM. Regulation of vascular endothelial growth factor expression in human colon cancer by interleukin-1beta. Br J Cancer 1999;80:1506–11.[Medline]

6 Mazure NM, Chen EY, Laderoute KR, Giaccia AJ. Induction of vascular endothelial growth factor by hypoxia is modulated by a phosphatidylinositol 3-kinase/Akt signaling pathway in Ha-ras-transformed cells through a hypoxia inducible factor-1 transcriptional element. Blood 1997;90:3322–31.[Abstract/Free Full Text]

7 Grugel S, Finkenzeller G, Weindel K, Barleon B, Marme D. Both v-Ha-Ras and v-Raf stimulate expression of the vascular endothelial growth factor in NIH 3T3 cells. J Biol Chem 1995;270:25915–9.[Abstract/Free Full Text]

8 Ellis LM, Staley CA, Liu W, Fleming RY, Parikh NU, Bucana CD, et al. Down-regulation of vascular endothelial growth factor in a human colon carcinoma cell line transfected with an antisense expression vector specific for c-src. J Biol Chem 1998;273:1052–7.[Abstract/Free Full Text]

9 Rak J, Mitsuhashi Y, Bayko L, Filmus J, Shirasawa S, Sasazuki T, et al. Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res 1995;55:4575–80.[Abstract]

10 Fontanini G, Boldrini L, Vignati S, Basolo F, Silvestri V, Lucchi M, et al. Bcl2 and p53 regulate vascular endothelial growth factor (VEGF)-mediated angiogenesis in non-small cell lung carcinoma. Eur J Cancer 1998;34:718–23.[Medline]

11 Bouvet M, Ellis LM, Nishizaki M, Fujiwara T, Liu W, Bucana CD, et al. Adenovirus-mediated wild-type p53 gene transfer down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in human colon cancer. Cancer Res 1998;58:2288–92.[Abstract]

12 Levy AP, Levy NS, Iliopoulos O, Jiang C, Kaplin WG Jr, Goldberg MA. Regulation of vascular endothelial growth factor by hypoxia and its modulation by the von Hippel–Lindau tumor suppressor gene. Kidney Int 1997;51:575–8.[Medline]

13 Mukhopadhyay D, Knebelmann B, Cohen HT, Ananth S, Sukhatme VP. The von Hippel–Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity. Mol Cell Biol 1997;17:5629–39.[Abstract]

14 Pal S, Claffey KP, Dvorak HF, Mukhopadhyay D. The von Hippel–Lindau gene product inhibits vascular permeability factor/vascular endothelial growth factor expression in renal cell carcinoma by blocking protein kinase C pathways. J Biol Chem 1997;272:27509–12.[Abstract/Free Full Text]

15 Howe A, Aplin AE, Alahari SK, Juliano RL. Integrin signaling and cell growth control. Curr Opin Cell Biol 1998;10:220–31.[Medline]



             
Copyright © 2000 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement