Disparities in localized malignant lung cancer surgical treatment: A population-based cancer registry analysis.

BACKGROUND: Lung cancer (LC) continues to be the leading cause of cancer deaths in the United States. Surgical treatment has proven to offer a favorable prognosis and a better 5-year relative survival for patients with early or localized tumors. This novel study investigates the factors associated with the odds of receiving surgical treatment for localized malignant LC in Tennessee. METHODS: Population-based data of 9679 localized malignant LC patients from the Tennessee Cancer Registry (2005-2015) were utilized to examine the factors associated with receiving surgical treatment for localized malignant LC. Bivariate and multivariate logistic regression analyses, cross-tabulation, and Chi-Square ( χ 2 ) tests were conducted to assess these factors. RESULTS: Patients with localized malignant LC who initiated treatment after 2.7 weeks were 46% less likely to receive surgery (adjusted odds ratio [AOR] = 0.54; 95% confidence interval [CI] = 0.50-0.59; p < 0.0001). Females had a greater likelihood (AOR = 1.14; CI = 1.03-1.24) of receiving surgical treatment compared to men. Blacks had lower odds (AOR = 0.76; CI = 0.65-0.98) of receiving surgical treatment compared to Whites. All marital groups had higher odds of receiving surgical treatment compared to those who were single/never married. Patients living in Appalachian county had lower odds of receiving surgical treatment (AOR = 0.65; CI = 0.59-0.71) compared with those in the non-Appalachian county. Patients with private (AOR = 2.09; CI = 1.55-2.820) or public (AOR = 1.42; CI = 1.06-1.91) insurance coverage were more likely to receive surgical treatment compared to self-pay/uninsured patients. Overall, the likelihood of patients receiving surgical treatment for localized malignant LC decreases with age. CONCLUSION: Disparities exist in the receipt of surgical treatment among patients with localized malignant LC in Tennessee. Health policies should target reducing these disparities to improve the survival of these patients.

Sociodemographic Factors and Health Insurance Coverage Are Associated with Invasive Breast Cancer in Tennessee: Appalachian and Non-Appalachian County Comparison.

Background: Tennessean women experience the 12th highest breast cancer (BC) mortality in the United States. Yet, few studies have examined BC outcomes among Tennessean women in and outside of Appalachia. We examined whether sociodemographic factors and health insurance status were associated with invasive BC in Tennessee by Appalachian and non-Appalachian county designation. Materials and Methods: Using the Tennessee Cancer Registry, we identified 52,187 women, aged ≥18, diagnosed with BC between 2005 and 2015. Multivariable logistic regression was performed to examine associations between invasive BC and sociodemographic characteristics, health insurance coverage, and county designation (Appalachian/non-Appalachian). Regression analyses stratified by county designation were subsequently performed. Results: In Tennessee, younger women had lower odds of invasive BC diagnosis (<45: odds ratio [OR] = 0.74, 95% confidence interval [CI] = 0.67-0.81; 55-64: OR = 0.91, 95% CI = 0.84-0.97) compared to women ≥65. Married Tennessean women had 12% (95% CI = 1.04-1.21) higher odds of invasive BC than single women. Further, both public (OR = 1.81, 95% CI = 1.41-2.33) and private (OR = 1.36, 95% CI = 1.06-1.76) health insurance were found to increase odds of invasive BC compared to no insurance/self-pay. Results from the subpopulation analyses were largely consistent with overall findings. In Appalachian counties, women on public health insurance had increased odds (OR = 1.42, 95% CI = 1.00-2.03) of invasive BC compared to uninsured/self-pay women, while in non-Appalachian counties, women insured both publicly (OR = 2.25, 95% CI = 1.57-3.24) and privately (OR = 1.68, 95% CI = 1.16-2.24) had increased odds of invasive BC. Conclusions: The results identify risk factors for Tennessean women in Appalachian and non-Appalachian counties whose malignancies evaded early detection, increasing risk of mortality.

Comparing proxy and formal measures of county-level racial isolation in race-stratified models: A case study in Tennessee, 2005-2014.

The purpose of this study was to understand whether proxy measures of county-level racial isolation (based on racial compositions) would yield similar results as the formal measures of county-level racial isolation (derived from the isolation index of P*). White (non-Hispanic White) and Black (non-Hispanic Black or African American) women residing in the State of Tennessee, USA, and diagnosed with a non-invasive or invasive breast cancer were considered as the study population. Individual-level variables were obtained from the Tennessee Cancer Registry data for the period between 2005 and 2014 (46,983 White women and 7,967 Black women), and county-level variables were obtained from the American Community Survey data for the periods of 2005-2009 and 2010-2014 (95 counties). Using breast cancer condition (non-invasive versus invasive) as the binary outcome of interest, a series of multilevel logistic regression analyses was conducted separately by race. After controlling for individual-level socio-demographic characteristics, proxy measure of county-level White isolation and county-level median household income were not associated with breast cancer condition, but formal measure of county-level White isolation was associated with lower odds of having an invasive breast cancer among White women. On the other hand, neither proxy nor formal measure of county-level Black isolation was associated with breast cancer condition, but county-level median household income was associated with lower odds of having an invasive breast cancer among Black women. These results suggest that using a proxy and formal measure of racial isolation may yield different results, and race-stratified analyses would be helpful for understanding a differential effect of racial isolation on Whites and Blacks. While more detailed examinations are needed in future studies, possible explanations on and reasons behind these findings are discussed.

Applying Latent Class Analysis on Cancer Registry Data to Identify and Compare Health Disparity Profiles in Colorectal Cancer Surgical Treatment Delay.

CONTEXT: Colorectal cancer (CRC) surgical treatment delay (TD) has been associated with mortality and morbidity; however, disparities by TD profiles are unknown. OBJECTIVES: This study aimed to identify CRC patient profiles of surgical TD while accounting for differences in sociodemographic, health insurance, and geographic characteristics. DESIGN: We used latent class analysis (LCA) on 2005-2015 Tennessee Cancer Registry data of CRC patients and observed indicators that included sex/gender, age at diagnosis, marital status (single/married/divorced/widowed), race (White/Black/other), health insurance type, and geographic residence (non-Appalachian/Appalachian). SETTING: The state of Tennessee in the United States that included both Appalachian and non-Appalachian counties. PARTICIPANTS: Adult (18 years or older) CRC patients (N = 35 412) who were diagnosed and surgically treated for in situ (n = 1286) and malignant CRC (n = 34 126). MAIN OUTCOME MEASURE: The distal outcome of TD was categorized as 30 days or less and more than 30 days from diagnosis to surgical treatment. RESULTS: Our LCA identified a 4-class solution and a 3-class solution for in situ and malignant profiles, respectively. The highest in situ CRC patient risk profile was female, White, aged 75 to 84 years, widowed, and used public health insurance when compared with respective profiles. The highest malignant CRC patient risk profile was male, Black, both single/never married and divorced/separated, resided in non-Appalachian county, and used public health insurance when compared with respective profiles. The highest risk profiles of in situ and malignant patients had a TD likelihood of 19.3% and 29.4%, respectively. CONCLUSIONS: While our findings are not meant for diagnostic purposes, we found that Blacks had lower TD with in situ CRC. The opposite was found in the malignant profiles where Blacks had the highest TD. Although TD is not a definitive marker of survival, we observed that non-Appalachian underserved/underrepresented groups were overrepresented in the highest TD profiles. The observed disparities could be indicative of intervenable risk.

Sociodemographic and Geographic Disparities of Prostate Cancer Treatment Delay in Tennessee: A Population-Based Study.

The relationship of social determinants of health, Appalachian residence, and prostate cancer treatment delay among Tennessee adults is relatively unknown. We used multivariate logistic regression on 2005-2015 Tennessee Cancer Registry data of adults aged ≥18 diagnosed with prostate cancer. The outcome of treatment delay was more than 90 days without surgical or nonsurgical intervention from date of diagnosis. Social determinants in the population-based registry were race (White, Black, Other) and marital status (single, married, divorced/separated, widow/widower). Tennessee residence was classified as Appalachian versus non-Appalachian (urban/rural). Covariates include age at diagnosis (18-54, 54-69, ≥70), health insurance type (none, public, private), derived staging of cancer (localized, regional, distant), and treatment type (non-surgical/surgical). We found that Black and divorced/separated patients had 32% (95% confidence interval [CI]: 1.22-1.42) and 15% (95% CI: 1.01-1.31) increased odds to delay prostate cancer treatment. Patients were at decreased odds of treatment delay when living in an Appalachian county, both urban (odds ratio [OR] = 0.89, 95% CI: 0.82-0.95) and rural (OR = 0.83, 95% CI: 0.78-0.89), diagnosed at ≥70 (OR = 0.59, 95% CI: 0.53-0.66), and received surgical intervention (OR = 0.72, 95% CI: 0.68-0.76). Our study was among the first to comprehensively examine prostate cancer treatment delay in Tennessee, and while we do not make clinical recommendations, there is a critical need to further explore the unique factors that may propagate disparities. Prostate cancer treatment delay in Black patients may be indicative of ongoing health and access disparities in Tennessee, which may further affect quality of life and survivorship among this racial group. Divorced/separated patients may need tailored interventions to improve social support.

Assessing health disparities in breast cancer incidence burden in Tennessee: geospatial analysis.

BACKGROUND: Tennessee women experience the 12th highest breast cancer mortality in the United States. We examined the geographic differences in breast cancer incidence in Tennessee between Appalachian and non-Appalachian counties from 2005 to 2015. METHODS: We used ArcGIS 10.7 geospatial analysis and logistic regression on the Tennessee Cancer Registry incidence data for adult women aged ≥ 18 years (N = 59,287) who were diagnosed with breast cancer from 2005 to 2015 to evaluate distribution patterns by Appalachian county designation. The Tennessee Cancer Registry is a population-based, central cancer registry serving the citizens of Tennessee and was established by Tennessee law to collect and monitor cancer incidence. The main outcome was breast cancer stage at diagnosis. Independent variables were age, race, marital status, type of health insurance, and county of residence. RESULTS: Majority of the sample were White (85.5%), married (58.6%), aged ≥ 70 (31.3%) and diagnosed with an early stage breast cancer (69.6%). More than half of the women had public health insurance (54.2%), followed by private health insurance coverage (44.4%). Over half of the women resided in non-Appalachian counties, whereas 47.6% were in the Appalachian counties. We observed a significant association among breast cancer patients with respect to marital status and type of health insurance coverage (p = < 0.0001). While the logistic regression did not show a significant result between county of residence and breast cancer incidence, the spatial analysis revealed geographic differences between Appalachian and non-Appalachian counties. The highest incidence rates of 997.49-1164.59/100,000 were reported in 6 Appalachian counties (Anderson, Blount, Knox, Rhea, Roane, and Van Buren) compared to 3 non-Appalachian counties (Fayette, Marshall, and Williamson). CONCLUSIONS: There is a need to expand resources in Appalachian Tennessee to enhance breast cancer screening and early detection. Using geospatial techniques can further elucidate disparities that may be overlooked in conventional linear analyses to improve women's cancer health and associated outcomes.

Changes in FXR1 expression after Chemotherapy for Rhabdomyosarcoma.

BACKGROUND: Rhabdomyosarcoma (RMS) arises from abnormal muscle development. We reported previously that Fragile-X-Related 1 (FXR1), essential to normal myogenesis, was highly expressed in RMS relative to other embryonal tumors. This current study explored FXR1 expression across RMS disease characteristics and treatment response. METHODS: RMS patients ≤18 years (1980-2019; n = 152) were categorized according to tumor histology, PAX/FOXO1 translocation, and vital status. FXR1 protein expression was compared before and after chemotherapy. Impact of FXR1 expression on relapse-free (RFS) and overall survival (OS) was analyzed. RESULTS: FXR1 was most intensely expressed in the cytosol of undifferentiated rhabdomyoblasts. At diagnosis, FXR1 expression was ubiquitous and strong across all disease characteristics and foremost associated with worse RFS in translocation-positive patients (p = 0.0411). Among embryonal and translocation-negative RMS, survivors showed a significantly greater decrease in FXR1 expression after chemotherapy (p < 0.001) compared to decedents (p = 0.8). In contrast, alveolar and translocation-positive RMS specimens showed insignificant changes in FXR1 expression across therapy. As expected, alveolar histology, translocation presence, stage, and clinical group associated with worse survival. CONCLUSIONS: FXR1 was expressed strongly across RMS specimens at diagnosis regardless of disease or patient characteristics, and particularly in undifferentiated cells. Reduction in FXR1 expression after chemotherapy associated with improved survival for embryonal and translocation-negative RMS patients.

Identifying Risk Profiles of Malignant Prostate Cancer Surgical Delay Using a Person-Centered Approach to Understand Prostate Cancer Disparities: The Constellation of Health Determinants Using Latent Class Analysis on Cancer Registry Data.

Surgical prostate cancer (PCa) treatment delay (TD) may increase the likelihood of recurrence of disease, and influence quality of life as well as survival disparities between Black and White men. We used latent class analysis (LCA) to identify risk profiles in localized, malignant PCa surgical treatment delays while assessing co-occurring social determinants of health. Profiles were identified by age, marital status, race, county of residence (non-Appalachian or Appalachian), and health insurance type (none/self-pay, public, or private) reported in the Tennessee Department of Health cancer registry from 2005 to 2015 for adults ≥18 years (N = 18,088). We identified three risk profiles. The highest surgical delay profile (11% of the sample) with a 30% likelihood of delaying surgery >90 days were young Black men, <55 years old, living in a non-Appalachian county, and single/never married, with a high probability of having private health insurance. The medium surgical delay profile (46% of the sample) with a 21% likelihood of delay were 55-69 years old, White, married, and having private health insurance. The lowest surgical delay profile (42% of the sample) with a 14% likelihood of delay were ≥70 years with public health insurance as well as had a high probability of being White and married. We identified that even with health insurance coverage, Blacks living in non-Appalachian counties had the highest surgical delay, which was almost double that of Whites in the lowest delay profile. These disparities in PCa surgical delay may explain differences in health outcomes in Blacks who are most at-risk.

Health disparities among tennessee pediatric renal tumor patients.

BACKGROUND/PURPOSE: Wilms tumor (WT) poses a cancer health disparity to black children globally, which has not been evaluated thoroughly for other pediatric renal cancers. We aimed to characterize health disparities among Tennessee children treated for any renal cancer. METHODS: The Tennessee Cancer Registry (TCR) was queried for patients ≤18 years having any renal cancer (n = 160). To clarify treatment and outcomes, we performed a retrospective cohort study of pediatric renal cancer patients in our institutional cancer registry (ICR; n = 121). Diagnoses in both registries included WT, Sarcoma/Other, and Renal Cell Carcinoma. Wilcoxon/Pearson, Kaplan-Meier, and logistic regression were completed. RESULTS: In both registries, WT comprised the most common renal cancer and youngest median age. Sarcoma was intermediate in frequency and age, and RCC was least common, having the oldest age (p < 0.001). In the TCR, black patients comprised 26% of all patients, presented more commonly with distant disease than white patients (37% v. 16%; p = 0.021), and showed worse overall survival (73% v. 89%; p = 0.018), while the ICR showed similar survival between race groups (92% v. 93%, p = 0.868). Sarcoma and metastases were independent predictors of death in both registries (p ≤ 0.002). CONCLUSIONS: Black children in Tennessee presented with more advanced disease and experienced worse survival when combining all renal cancer types, particularly RCC and Sarcoma. When treated at a comprehensive pediatric cancer center, these survival disparities appear diminished. TYPE OF STUDY: Prognostic study. LEVEL OF EVIDENCE: Level II (retrospective cohort).

Improving Knowledge and Awareness of Human Papillomavirus-Associated Gynecologic Cancers: Results from the National Comprehensive Cancer Control Program/Inside Knowledge Collaboration.

BACKGROUND: Over 16,000 women are diagnosed with a human papillomavirus (HPV)-associated gynecologic cancer every year. Because most of these cancers are preventable, correct and appropriate information about the HPV vaccine and cervical cancer screening can help reduce incidence. MATERIALS AND METHODS: The Centers for Disease Control and Prevention created Inside Knowledge: Get the Facts About Gynecologic Cancer campaign materials, which were used by seven National Comprehensive Cancer Control Program recipients in tailored educational sessions on gynecologic cancer with women and healthcare providers in the community setting. Session participants completed presession and postsession questionnaires. Differences in knowledge and intentions were assessed using chi-square tests for women in the general public, obstetricians/gynecologists (OB/GYNs), primary care physicians (PCPs), and other healthcare providers. RESULTS: Women's knowledge improved significantly presession to postsession that HPV causes vaginal (39%-65%, p < 0.001) and vulvar cancers (26%-60%, p < 0.001), but postsession few women correctly identified all HPV-associated gynecologic cancers (15%). From presession to postsession, more women were able to correctly identify recommended age groups for whom the HPV vaccine is recommended (15%-30%, p < 0.001), and that the Pap test only screens for cervical cancer (58%-73%, p < 0.001). Among providers, OB/GYNs had more baseline knowledge of HPV-associated gynecologic cancers than other providers. Postsession, PCPs and other providers increased their knowledge of HPV vaccine recommended age groups (33%-71% and 23%-61%, respectively), and the 3-year recommended screening interval for the Pap test (73%-91% and 63%-85%, respectively). HPV vaccine knowledge did not show significant improvement among OB/GYNs postsessions. CONCLUSIONS: Women and healthcare providers who attended the Inside Knowledge sessions significantly improved their knowledge of HPV-associated gynecologic cancers. Additional educational activities during the sessions that support distinguishing between HPV-associated versus other gynecologic cancers and clarify HPV vaccine recommendations may help with further increases in knowledge.

Cancer Registries: Can We Improve the Quality of Thyroid Cancer Data?

BACKGROUND: Cancer registries are used to report cancer care trends and outcomes. Information from these data sets is utilized to craft practice guidelines and management recommendations. Limited knowledge is available regarding the quality of the data contained within registries. We sought to determine the accuracy of a single variable, 'surgery of the primary site', in the Tennessee Cancer Registry (TCR). METHODS: A retrospective review of the TCR thyroid database was performed. Hospital facilities were classified as either Commission on Cancer (CoC) or non-CoC accredited. Certified Tumor Registrars at the TCR reviewed the abstracted text and/or telephoned the reporting facility staff to confirm the definitive thyroid procedure. RESULTS: A total of 921 thyroid cancer cases, diagnosed/treated at TN facilities during 2004-2011, were coded with thyroid lobectomy (TL). Overall, 369 (40 %) were incorrectly coded, of which 247(67 %) were changed to total thyroidectomy. The majority of cases (80 %) were reported by CoC facilities. When compared by facility type, 42 % of records submitted from CoC facilities contained incorrect codes for the variable 'surgery of the primary site' TL compared with 34 % of records submitted by non-CoC facilities (p = 0.047). CONCLUSION: In this study of the TCR, 40 % of records contained inaccurate coding of the variable 'surgery of the primary site'. Upon validation, 27 % of all records were changed from TL to total thyroidectomy. The rate of incorrect coding was higher in CoC reporting facilities than in non-CoC facilities. Using text-to-code re-abstraction audits and facility contact these discrepancies can be validated and corrected to improve data quality.

The effect of health insurance status on the treatment and outcomes of patients with colorectal cancer.

BACKGROUND AND OBJECTIVES: Uninsured and underinsured cancer patients often have delayed diagnosis and inferior outcomes. As healthcare reform proceeds in the US, this disparity may gain increasing importance. Our objective was to investigate the impact of health insurance status on the presentation, treatment, and survival among colorectal cancer (CRC) patients. METHODS: A total of 10,692 patients diagnosed with CRC between 2004 and 2008 identified from the Tennessee Cancer Registry were stratified into five groups: Private, Medicare, Military, Medicaid, and uninsured. Multivariable regression models were constructed to test the association of insurance with receipt of recommended adjuvant therapy and overall survival (OS). RESULTS: Uninsured and Medicaid patients were more often African American (AA) and presented with higher stage tumors (P < 0.001). Medicare patients were less likely to receive recommended adjuvant therapy (OR 0.54). Lack of insurance, Medicaid, and failure to receive recommended adjuvant therapy were independently associated with worse OS. CONCLUSIONS: Although uninsured and Medicaid patients receive recommended adjuvant therapy comparable to other patients, they present with later stage disease and have a worse OS. Future studies are needed to better explain these disparities especially in the light of changing healthcare climate in the US.

Race disparities in Wilms tumor incidence and biology.

BACKGROUND: Wilms tumor (WT) is thought to arise in children of Black African ancestry with greater frequency than in Whites. To clarify the biological basis for race disparities in WT, we first verified that Black children residing in Tennessee have an increased incidence of WT, and second, established molecular profiles in WT that are specific to race. MATERIALS AND METHODS: To assess race disparities in WT epidemiology, the Tennessee Cancer Registry (TCR) was queried for all in-state patients less than 20 y of age and registered between 1999 and 2008. To explore race disparities in WT biology, six Black and four White WT specimens acquired in Tennessee were analyzed using imaging mass spectrometry (IMS). RESULTS: TCR data show that Black children are over-represented among WT patients (29%) relative to all other childhood cancers (18.5%; P = 0.01). WT ranked the fifth most common cancer diagnosis among Blacks, but ninth among Whites. The diagnosis of WT occurred 79% more frequently among Blacks (n = 28) than Whites (n = 69; P = 0.01), and proportionally more Blacks tended to present with distant disease. Although overall survival from WT was not statistically different between Blacks (92.9%) and Whites (94.0%), Black males showed the lowest survival (85%; P = 0.21). IMS analysis identified peptide spectra from both WT blastema and stroma that independently classify specimens according to race with greater than 80% accuracy. CONCLUSIONS: In Tennessee, Black children appear more susceptible than Whites to develop WT. Race-specific molecular profiles can be determined that may help to clarify pathways of Wilms tumorigenesis and the biological basis for race disparities in WT incidence and biology.

Health insurance status affects staging and influences treatment strategies in patients with hepatocellular carcinoma.

BACKGROUND: Lack of health insurance is associated with poorer outcomes for patients with cancers amenable to early detection. The effect of insurance status on hepatocellular carcinoma (HCC) presentation stage and treatment outcomes has not been examined. We examined the effect of health insurance status on stage of presentation, treatment strategies, and survival in patients with HCC. METHODS: The Tennessee Cancer Registry was queried for patients treated for HCC between January 2004 and December 2006. Patients were stratified by insurance status: (1) private insurance; (2) government insurance (non-Medicaid); (3) Medicaid; (4) uninsured. Logistic, Kaplan-Meier, and Cox models tested the effects of demographic and clinical covariates on the likelihood of having surgical or chemotherapeutic treatments and survival. RESULTS: We identified 680 patients (208 private, 356 government, 75 Medicaid, 41 uninsured). Uninsured patients were more likely to be men, African American, and reside in an urban area (all P < 0.05). The uninsured were more likely to present with stage IV disease (P = 0.005). After adjusting for demographics and tumor stage, Medicaid and uninsured patients were less likely to receive surgical treatment (both P < 0.01) but were just as likely to be treated with chemotherapy (P ≥ 0.243). Survival was significantly better in privately insured patients and in those treated with surgery or chemotherapy (all P < 0.01). Demographic adjusted risk of death was doubled in the uninsured (P = 0.005). CONCLUSIONS: Uninsured patients with HCC are more likely to present with late-stage disease. Although insurance status did not affect chemotherapy utilization, Medicaid and uninsured patients were less likely to receive surgical treatment.

Human papillomavirus and molecular considerations for cancer risk.

Human papillomaviruses (HPVs) are a major cause of cancer globally, including cervical cancer. The HPV 'early' proteins, E6 and E7, are the chief oncoproteins involved in cancer progression. These oncoproteins are more highly expressed in high-grade dysplasias and invasive cancer coincident with reduced viral DNA replication and reduced production of infective progeny virions. The E6 and E7 oncoproteins interact with several cellular proteins-classically TP53 and RB1, respectively-leading to the degradation of several of these proteins, although all interactions do not necessarily result in the degradation of a cellular protein. HPV infection is also associated with viral and host DNA methylation changes, many of which also occur in cancer types not associated with HPV infection. The E6 and E7 interactions with cellular proteins and DNA methylation changes are associated with changes in the integrity of key cellular pathways that regulate genomic integrity, cell adhesion, the immune response, apoptosis, and cell cycle control. The alterations in key cellular pathways may provide useful biomarkers to improve the sensitivity of current cancer screening methods, such as the Papanicolaou test. This review provides a detailed summary of the interactions of E6 and E7 with cellular proteins and alterations in cellular DNA methylation associated with HPV infection. The importance of molecular biomarkers to the clinical setting, underserved populations, and general public health is discussed.

Extracellular matrix and HIF-1 signaling: the role of prolidase.

Hypoxia-inducible factor-1 (HIF-1) plays an important role in stress-responsive gene expression. Although primarily sensitive to hypoxia, HIF-1 signaling can be regulated by a number of stress factors including metabolic stress, growth factors and molecules present in the extracellular matrix (ECM). Degradation of ECM by metalloproteinases (MMP) is important for tumor progression, invasion and metastasis. ECM is predominantly collagen, and the imino acids (Pro and HyPro) comprise 25% of collagen residues. The final step in collagen degradation is catalyzed by prolidase, the obligate peptidase for imidodipeptides with Pro and HyPro in the carboxyl terminus. Defective wound healing in patients with inherited prolidase deficiency is associated with histologic features of angiopathy suggesting that prolidase may play a role in angiogenesis. Because HIF-1 alpha is central to angiogenesis, we considered that prolidase may modulate this pathway. To test this hypothesis, we made expression constructs of human prolidase and obtained stable transfectants in colorectal cancer cells (RKO). Overexpression of prolidase resulted in increased nuclear hypoxia inducible factor (HIF-1 alpha) levels and elevated expression of HIF-1-dependent gene products, vascular endothelial growth factor (VEGF) and glucose transporter-1 (Glut-1). The activation of HIF-1-dependent transcription was shown by prolidase-dependent activation of hypoxia response element (HRE)-luciferase expression. We used an oxygen-dependent degradation domain (ODD)-luciferase reporter construct as a surrogate for HIF-1 alpha as an in situ prolyl-hydroxylase assay. Since this reporter is degraded by VHL-dependent mechanisms, the increased levels of luciferase observed with prolidase expression reflected the decreased HIF-1 alpha prolyl hydroxylase activity. Additionally, the differential expression of prolidase in 2 breast cancer cell lines showed prolidase-dependent differences in HIF-1 alpha levels. These findings show that metabolism of imidodipeptides by prolidase plays a previously unrecognized role in angiogenic signaling.

Intrinsic cisplatin resistance in lung and ovarian cancer cells propagating in medium acutely depleted of folate.

Many tumors develop intrinsic and/or acquired resistance to cisplatin. The purpose of the present study was to examine the influence of acute extracellular folate depletion prior to cisplatin treatment on the development of intrinsic cisplatin resistance. Lung and ovarian cancer cells were propagated in medium acutely depleted of folate and subsequently treated with cisplatin. The IC50 level for cisplatin, cell viability, cell proliferation, and global DNA methylation were determined. Gene expression profiling was performed using the Atlas Cancer 1.2 Array. Acute extracellular folate depletion resulted in the development of intrinsic cisplatin resistance. Cells propagating in medium acutely depleted of folate had a survival advantage compared to control cells when exposed to cisplatin, and thymidine supplementation did not reverse the intrinsic cisplatin resistance. cDNA microarray analysis revealed some novel genes associated with the development of intrinsic cisplatin resistance. Our report is the first to demonstrate that acute extracellular folate depletion results in intrinsic cisplatin resistance. If these results are confirmed by in vivo human studies, it would suggest that the folate status of the recipient of cisplatin might have an impact on response to that chemotherapeutic agent.

Micronutrients and cancer therapy.

The effect of micronutrient supplementation on the effectiveness of cancer chemotherapeutic agents is reviewed, and the efficacy of antioxidants, folic acid, and other vitamins and minerals is discussed. Although some micronutrients show promise in enhancing the cytotoxicity of anticancer agents in vitro, caution should be exercised in recommending micronutrient supplementation for cancer patients receiving chemotherapeutic drugs. To date, few well-controlled clinical trials have been conducted to evaluate the efficacy of micronutrients in promoting the sensitivity of tumors to chemotherapeutic agents.