The impact of hypoxia (low oxygen) on tumor initiation and resistance to therapy.
Oxygen is a critical cellular nutrient, fueling metabolic activity and serving as a signaling molecule in numerous systems. In the atmosphere, oxygen makes up about 21% of the air at sea level. In the body, oxygen contents vary from the highest levels in the alveoli of the lungs (~14%) down to the lowest levels (0.5-1%) in parts of the brain, heart, kidneys, and in stem cell niches throughout the body. This gradient of oxygen plays an important role in development and differentiation, as well as maintaining tissue architecture. In pathologies such as cancer, oxygen homeostasis is frequently disrupted. As tumors reach the size of a few millimeters, blood supply becomes limiting and areas of hypoxia occur. This behavior is characteristic of nearly all solid tumors, and the degree of hypoxia correlates strongly with tumor aggressiveness and patient outcome.
Hypoxia induces molecular adaptations that have effects on cells, tissues, and the entire organism. Most notably, a family of transcriptional regulators (the hypoxia inducible factors, or HIF) is stabilized under hypoxic conditions, leading to the alteration of gene expression patterns that control functions as varied as glycolysis, angiogenesis, and erythropoeisis. Together, these factors modulate the adaptations to hypoxia. While important responses to cellular and tissue damage, these functions also frequently contribute to tumorigenesis.
Tumor initiation is tightly controlled by well-established tumor suppressor pathways. The vast majority of oncogenic events never progress; only in extremely rare cases do aberrant cells manage to circumvent the action of cell cycle regulatory proteins and result in cancer development. In fact in most cases oncogene activation leads to cellular senescence, a tumor suppressor response characterized by an irreversible state of cell cycle arrest. Interestingly, this phenomenon of oncogene-induced senescence has recently been found to depend on oxygen, such that high levels of oxygen promote senescence while low levels inhibit it. This is an intriguing finding given that the oxygen content of the body varies over a large range. Oxygen levels that are permissive for oncogene activation are well within the normal range of oxygen in various tissues, suggesting that oxygen may regulate the tolerance for oncogenic events in vivo. It is unclear how hypoxia can diffuse the induction of senescence.
Hypoxia and Senescence:
One of the projects in the lab is to understand the contribution of normal tissue hypoxia to tumor initiation. We are focusing on oncogene-induced senescence from several well known oncogenes, and investigating how the molecular pathways that mediate senescence are affected by hypoxia. One of the organs of our particular interest is the kidney, where clear cell renal carcinoma, a tumor associated with constitutive activation of the hypoxia response system through the frequent inactivation of the VHL tumor suppressor protein, develops. The kidney demonstrates relatively low normal oxygen content in the inner medulla and higher levels in the outer cortex.
Recent findings have identified tumor stem cell components to various cancers; these cells are theorized to be critical to tumor development and maintenance. The knowledge that normal stem cells require hypoxia to maintain "stemness" (and indeed that tumor stem cells reside in hypoxic regions of tumors) has led us to hypothesize that it may be these cells that are prone to oncogenic transformation. Elucidating how and when cells in the body decide to undergo senescence is critical to understanding tumor suppression in vivo, as well as how to potentially reactivate this process in established cancers.
Hypoxia and Resistance to Therapy:
One of the complications of hypoxia in tumors is its correlation with resistance to therapy. In fact radiation effects in cells are highly dependent on the presence of molecular oxygen to "fix" damage in DNA and bring about cell death. This oxygen effect is a classic feature of radiation biology. In addition to the physical dynamics of radiation damage, hypoxia also contributes to radiation resistance through molecular pathways. A second line of investigation in the lab is to identify genetic mediators of radiation resistance in glioblastoma, a highly radio-resistant disease, for which radiation therapy remains a primary treatment modality. Our goal is to develop adjuvant therapies that will increase the effectiveness of radiation treatment.
- Haksoo Kim, Jeffrey Fabien, Yiran Zheng, Jake Yuan, James Brindle, Andrew Sloan, Min Yao, Simon Lo, Barry Wessels, Mitchell Machtay,Â Scott Welford*, Jason W. Sohn*. Establishing a Process of Irradiating Small Animals Using a CyberKnife and a Micro-CT Scannerl.Â Â Medical Physics.Â 2014. 41: 021715.
- Vinay Pasupuleti, Weinan Du, Yashi Gupta, I-Ju Yeh, Monica Montano, Cristina Magi-Galuzzi, and Scott M. Welford. Dysregulated D-Dopachrome Tautomerase, a Hypoxia Inducible Factor-Dependent Gene, Cooperates with Macrophage Migration Inhibitory Factor in Renal Tumorigenesis. Journal of Biological Chemistry. 2013. 289: 3713-23.
- I-Ju Yeh, Ndiya Ogba, Scott M. Welford and Monica M. Montano. HEXIM1 downregulates HIF-1Î± protein stability. Biochemical Journal. 2013. 456:195-204.
- Weinan Du, Bradley M. Wright, Xiaofeng Li, James Finke, Brian I. Rini, Ming Zhou, Huiying He, Priti Lal, and Scott M. Welford. Tumor derived macrophage migration inhibitory factor promotes an autocrine loop that enhances renal cell carcinoma. Oncogene. 2013. 32: 1469-74.
- Scott M. Welford and Amato J. Giaccia. Hypoxia and senescence: the impact of oxygenation on tumor suppression. Molecular Cancer Research. 2011. 9: 538-44
- Scott M. Welford, Mary Jo Dorie, Xiaofeng Li, and Amato J. Giaccia. Renal Oxygenation Suppresses VHL-Loss-Induced Senescence that is Caused by Increased Sensitivity to Oxidative Stress. Molecular and Cellular Biology. 2010. 30:4595-603.
- Lucas Donovan, Scott M. Welford, John Haaga, Joseph LaManna, and Kingman P. Strohl. Hypoxia-implications for pharmaceutical developments. Sleep and Breathing. 2010. 14: 269-8.
- Xin Huang, Lianghao Ding, Kevin L. Bennewith, Ricky T. Tong, Scott M. Welford, K. Kian Ang, Michael Story, Quynh-Thu Le, and Amato J. Giaccia. Hypoxia-inducible mir-210 regulates normoxic gene expression involved in tumor initiation. Molecular Cell. 2009. 35: 856-67.
- Barbara Bedogni, Scott M. Welford, Andrea C. Kwan, James Ranger-Moore, Kathylynn Saboda, and Marianne Broome Powell. Inhibition of phosphatidylinositol-3-kinase and mitogen-activated protein kinase kinase 1/2 prevents melanoma development and promotes melanoma regression in the transgenic TPRas mouse model. Molecular Cancer Therapeutics. 2006 5: 3071-3077.
- Scott M. Welford, Barbara Bedogni, Katarina Gradin, Lorenz Poellinger, Marianne Broome Powell, and Amato J. Giaccia. HIF1alpha delays premature senescence through the activation of MIF. Genes and Development. 2006. 20: 3366-3371.
- Rachel A. Freiberg, Ester M. Hammond, Mary Jo Dorie, Scott M. Welford, and Amato J. Giaccia. DNA damage during reoxygenation elicits a Chk2-dependent checkpoint response. Molecular and Cellular Biology. 2006. 26: 1598-1609
- Barbara Bedogni, Scott M. Welford, David S. Cassarino, Brian J. Nickoloff, Amato J. Giaccia, and Marianne Broome Powell. The hypoxic microenvironment of the skin contributes to Akt-mediated melanocyte transformation. Cancer Cell. 2005. 8: 443-454.
- Barbara Bedogni, Melony S. O'Neill, Scott M. Welford, Donna M. Bouley, Amato J. Giaccia, Nicolas C. Denko, and Marianne B. Powell. Topical treatment with inhibitors of the phosphatidylinositol 3'-kinase/Akt and Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways reduces melanoma development in severe combined immunodeficient mice. Cancer Research. 2004. 64: 2552-60.