HEAD & NECK SURGERY - Stanford University School of Medicine

More documents

Recommendations

Info

S T ANFORD U NIVERSITY D EPARTMENT OF O TOLARYNGOLOGY– HEAD & N ECK S URGERY R ESEARCH P ROGRAMS THE POSSIBLE ROLE OF STEM CELLS IN HEAD & NECK CANCER Michael Kaplan, MD, Michael Clarke, MD, Laurie Ailles, PHD Willard Fee, MD, Ranjiv Sivanidan, MD, Mark Prince, MD Head and neck cancer affects 50,000 Americans annually and remains a devastating world-wide killer. In India, for example, it is the leading cause of cancer deaths. Cisplatin-based concomitant chemotherapy and selected monoclonal antibodies have improved locoregional controls compared to irradiation alone, but there has been little to no impact on survival because of distant metastasis and the therapy-resistant recurrences. Why has there been so little progress? Is it because we have not adequately enough appreciated the underlying tumor biology so as to develop more effective therapeutic approaches? H&E and immunoperodixase staining of CD44 in passaged cells growing as explant It has been understood for quite some time that leukemias and lymphomas arise within hematopoietic stem cells, yet it has been only recently that a cancer stem cell (CSC) hypothesis has been extended to solid epithelial cells, including head and neck squamous cell carcinomas (HNSCC). Normal stem cells maintain an organ’s stem cell pool by self-renewing, while generating large numbers of mature daughter differentiated cells that in their life cells in time undergo apoptosis (programmed cell death). Squamous epithelium is comprised of a basal layer of cells that contain some stem cells and overlying layers that contain daughter cells that die as they approach the surface. When stem cells divide they asymmetrically give rise to both a committed daughter cell as well as another stem cell. This stem cell must avoid programmed cell death (apoptosis) throughout the organism’s lifetime. Under normal circumstances it also must recognize its neighbors in order to know 8 when to divide and when not to; in other words cell-cell signaling pathways are likely important. Stem cells (or their immediate daughters) also must be able to migrate, both upward in the epithelium and in response to trauma. These three properties – avoiding apoptosis, critical cell-cell signaling, and migration – are also key attributes of developmental (embryonic, fetal) stem cells. An important insight is that avoiding apoptosis and migration are also key characteristics of cancer cells; and aberrant cell-cell signaling pathways are beginning to be shown as well. A cancer stem cell hypothesis suggests that cancer is a result of inadequately controlled proliferation of the stem cells themselves, and not the heterogeneous mix of daughter cells. Such aberrant growth would lead to subpopulations that contain a small percentage of daughter stem cells but many more committed differentiated cells that will undergo apoptosis in time. In other words, one should expect to see functional heterogeneity, with only a small fraction of cells harboring tumorigenic potential. This had been known in hematological malignancies for 40 years, but was shown in solid tumors (medulloblastoma, breast cancer) only in the past three years. Only CD44+ cells serially maintain clonogenicity. Working along similar lines using methods employed to identify cancer stem cells in breast cancer, collaborating laboratories at the University of Michigan and at Stanford showed in 2006 (in press) that this is also true for HNSCC. HNSCC contains a distinct population of cancer stem cells with the exclusive ability to produce tumors in mice and recreate the original tumor heterogeneity. They are clonogenic in vitro (Fig 1) and initiate tumors in vivo (Fig 2), while the remaining cells in the tumor do not share these properties. This population is distinguished by a cell surface marker (CD44) that distinguishes these cells from the other epithelial cells within the tumor that lack clonogenicity. The identification of cancer stem cells in HNSCC has important ramifications. Most basically, it lends further support to the general concept that a CSC model is true for all cancers. Second, it suggests one possible reason why chemotherapy has been disappointing is that the assay used clinically (and in some clonogenic assays) is overall tumor response, whereas it is not overall but rather stem cell response that is key. Third, it suggests that characterizing selected key molecular pathways that are involved in selfrenewal, such as cell-cell signaling pathways, should provide insights into specifically what is abnormally regulated. Insights such as these hold promise for the development of new treatment strategies targeted not against the majority of tumor cells (which have limited tumorigenicity) but against the critical population of cancer stem cells that is the key culprit. A fourth striking implication of validating a CSC model is that one cannot help but see the striking similarities between normal embryonic development and normal stem cells and their dysregulation that is cancer. This suggests that understanding normal development should lead to insight into cancer, and vice versa. The cellular genetic control mechanisms seen in normal development, stem cell regulation, and cancer are likely to be the same. In the past decade an entirely new layer of intranuclear genetic control has been identified-small RNAs regulate gene expression by suppressing homologous or near-homologous DNA sequences.
These microRNAs (miRNA) are normal, and derive from pre-miRNA genes within us, and the RNA-protein machinery all organisms use for this is being increasingly identified. MiRNA gene chips are available, and abnormal quantities of selected miRNAs have begun to be identified in a few malignancies. That miRNAs are stable in paraffin will allow investigation of archived material as well as easier investigation of fresh tumor-banked material. The recognition of cancer stem cells in solid tumors, including head and neck carcinomas, and the advances in DNA control by miRNAs suggest reasons for optimism that fundamental insights will lead to genetic therapies targeting cancer stem cells in the future. Our lab, as well as others, will investigate whether CD44 (a complex molecule, with multiple splice variants, that is involved in cell adhesion and mobility) is simply a marker for CSCs, or whether it plays an essential function. More specific markers are likely to be found, which in aggregate will better identify the stem cell pool. As identification of stem cells becomes more precise, investigation of abnormal miRNAs will be a goal. As abnormalities in cell-cell signaling pathways become better understood, it will be of interest to look at differences between tumors and pre-malignant conditions such as dysplasia and inverted papilloma, as well as the differences in pathways associated with motility between primary tumors and both nodal and distant metastases. In summary, the initial validation of cancer stem cells in head and neck carcinomas offers myriad opportunities both to understand the fundamental nature of cancer and to develop stem cell targets for genetic in the future. HIGH SPEED LARYNGEAL IMAGING & THE VIRTUAL LARYNGOSCOPE Yuling Yan, PhD & Edward Damrose MD The primary objective of our research program is to understand the mechanism of phonation for normal and for pathological voice conditions. We employ an interdisciplinary approach to these studies that borrows and integrates concepts and methodologies from bioengineering, biophysics, mathematical modeling and physiology. Functional Analysis and Modeling of Phonation in Normal and Diseased States Vibration of the vocal folds is an essential yet poorly understood event in human voice production. An important aspect of our research program is to characterize the dynamic behavior of the vocal folds during phonation – the ultimate goal for these studies is to understand the mech- Figure 1 – (Top) A montage of 10 image frames from an HSKI recording of a normal subject while producing a sustained vowel phonation; (Bottom) Spatially resolved vocal fold vibration representing diplophonic voice, and Nyquist pattern showing the bifurcation (transition from a normophonic [red] to a diplophonic phase [black]). anism of phonation in terms of the generation and interaction of sound waves in the vocal system; these studies will lead to the development of quantitative biomechanical models of vocal fold dynamics and acoustic interactions in the vocal tract for the detection, diagnosis and assessment of treatments for specific voice disorders. Fall 2006 Quantitative analysis of vocal fold dynamics using High Speed Digital Imaging (HSDI) HSDI with simultaneously acquired acoustic recordings are being used to characterize vocal fold dynamics. We have developed new methods and software platforms to generate comprehensive, functional analysis of vocal fold vibrations from HSDI and acoustic recordings. For example, our analytical platform that integrates automatic image segmentation of the vocal folds and detection of vocal fold edge (Figure 1) with the generation of glottal waveforms that include the glottal area waveform, glottal width function and displacements of the leftright vocal fold edges at specific anterior-medial-posterior locations. The approach also integrates our ‘Nyquist’ plot based waveform analysis (Yan et al., 2005. J. Voice), which provides not only an at-a-glance assessment of the vibratory properties of the vocal fold (Figure 1, bottom right) but a comprehensive and quantitative,high-resolution description of the vibratory properties of the vocal fold for diagnosing specific voice disorders and assessment of therapies. A related analysis has been described for acoustic signals (Yan et al, 2006. J. Voice). These studies are advancing towards a better understanding of voicing and are currently under clinical evaluation for the differential diagnosis of voice disorders associated with neurological disease and the aging process. A near-term research goal is to develop a large, comprehensive and comparative database of dynamic characteristics of vocal folds derived from our image and acoustic-based analyses that will be used to correlate changes in the 9
Page 1 and 2: Stanford University Medical Center
Page 3 and 4: I NTRODUCING O UR FACULTY (Fall 200
Page 5 and 6: STANFORD FACULTY AT SANTA CLARA VAL
Page 7: may act to amplify low levels of so
Page 11 and 12: of maternal senescent red blood cel
Page 13 and 14: EVIDENCE-BASED MEDICINE IN FACIAL P
Page 15 and 16: Non-invasive Diagnosis of Cholestea

HEAD & NECK SURGERY - Stanford University School of Medicine

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?