Hyperthermia on mesenchymal stem cells (MSCs) can sensitize tumor cells to undergo cell death†

Hyperthermia, the procedure of raising the temperature of tumor-loaded tissue to 40°–43°C, has been applied to various established cancer treatments. Although the mechanism of hyperthermia in cancer treatment is well-known, there are few or no studies regarding the effect of hyperthermia on the tumor-supportive stroma. Mesenchymal stem cells (MSCs) display the potential for differentiation into various tissues. MSCs are also reported to play a role as potential precursors for tumor stroma in providing a favorable environment for tumor progression. Here, we investigated the effects of hyperthermia-treated MSCs on the viability and growth of cancer cells. Culture supernatants from non-shocked or heat-shocked MSCs (NS-MSCs or HS-MSCs) were added to MCF7 cells. Morphological analysis and cell proliferation assay showed the reduced viability and growth of MCF7 cells by addition of culture medium conditioned by HS-MSCs. Additionally, exposure to the conditioned medium by HS-MSCs induced cell cycle arrest at G2/M phase, increased MHC class I, Fas receptor, and TNF-R expressions, and decreased MDR1 expression in the MCF7 cells. In particular, the conditioned medium of HS-MSCs accelerated the inhibition of tumor cell growth by several chemotherapeutic drugs. These data present new aspects of hyperthermia in cancer treatment, suggesting that hyperthermia can enable tumor stroma provide a sensitizing environment for tumor cells to undergo cell death.     

Mesothelial cells induce the motility of human ovarian carcinoma cells

The dissemination of ovarian carcinoma cells within the abdominal cavity involves interaction of tumor cells with the peritoneal mesothelium. The aim of our study was to investigate whether mesothelial cells might directly affect the spreading of this tumor by inducing motility and invasiveness of human ovarian carcinoma cells. Serum‐free supernatants of cultured human mesothelial cells [conditioned medium (CM)] induced chemotaxis and invasiveness of the human ovarian carcinoma cell lines SK‐OV‐3, OVCAR‐5 and A2780 in a Boyden chamber. Checkerboard analysis indicated that the stimulated motility was prevalently directional. Most of the chemotactic activity was retained by a heparin affinity column, indicating that the motility factor(s) is a heparin‐binding protein. Using different monoclonal antibodies (MAbs) directed against chemotactic factors that are secreted by mesothelial cells, we found that chemotaxis was partially prevented (64.8% inhibition) by antibodies against fibronectin (FN). CM also induced haptotactic migration of ovarian carcinoma cells, and anti‐FN antibodies significantly inhibited haptotaxis. The presence of FN in the CM was confirmed by Western blot analysis. Our findings suggest that mesothelium plays an active role in inducing the intraperitoneal spread of ovarian carcinoma cells, and point to FN as being one of the main mediators of mesothelium‐induced ovarian carcinoma cell motility. Int. J. Cancer 80:303–307, 1999. © 1999 Wiley‐Liss, Inc.     

Mesenchymal stem cells enhance growth and metastasis of colon cancer

Recently, mesenchymal stem cells (MSCs) were reported to migrate to tumor stroma as well as injured tissue. We examined the role of human MSCs in tumor stroma using an orthotopic nude mice model of KM12SM colon cancer. In in vivo experiments, systemically injected MSCs migrated to the stroma of orthotopic colon tumors and metastatic liver tumors. Orthotopic transplantation of KM12SM cells mixed with MSCs resulted in greater tumor weight than did transplantation of KM12SM cells alone. The survival rate was significantly lower in the mixed‐cell group, and liver metastasis was seen only in this group. Moreover, tumors resulting from transplantation of mixed cells had a significantly higher proliferating cell nuclear antigen labeling index, significantly greater microvessel area and significantly lower apoptotic index. Splenic injection of KM12SM cells mixed with MSCs, in comparison to splenic injection of KM12SM cells alone, resulted in a significantly greater number of liver metastases. MSCs incorporated into the stroma of primary and metastatic tumors expressed α‐smooth muscle actin and platelet‐derived growth factor receptor‐β as carcinoma‐associated fibroblast (CAF) markers. In in vitro experiments, KM12SM cells recruited MSCs, and MSCs stimulated migration and invasion of tumor cells through the release of soluble factors. Collectively, MSCs migrate and differentiate into CAFs in tumor stroma, and they promote growth and metastasis of colon cancer by enhancing angiogenesis, migration and invasion and by inhibiting apoptosis of tumor cells.     

Radiolabeled liposome imaging determines an indication for liposomal anticancer agent in ovarian cancer mouse xenograft models

Liposomal anticancer agents can effectively deliver drugs to tumor lesions, but their therapeutic effects are enhanced in only limited number of patients. Appropriate biomarkers to identify responder patients to these liposomal agents will improve their treatment efficacies. We carried out pharmacological and histopathological analyses of mouse xenograft models bearing human ovarian cancers (Caov‐3, SK‐OV‐3, KURAMOCHI, and TOV‐112D) to correlate the therapeutic effects of doxorubicin‐encapsulated liposome (Doxil^®) and histological characteristics linked to the enhanced permeability and retention effect. We next generated ¹¹¹In‐encapsulated liposomes to examine their capacities to determine indications for Doxil^® treatment by single‐photon emission computed tomography (SPECT)/CT imaging. Antitumor activities of Doxil^® were drastically enhanced in Caov‐3, moderately in SK‐OV‐3, and minimally in KURAMOCHI and TOV‐112D when compared to doxorubicin. Microvessel density and vascular perfusion were high in Caov‐3 and SK‐OV‐3, indicating a close relation with the enhanced antitumor effects. Next, ¹¹¹In‐encapsulated liposomes were given i.v. to the animals. Their tumor accumulation and area under the curve values over 72 h were high in Caov‐3, relatively high in SK‐OV‐3, and low in two other tumors. Importantly, as both Doxil^® effects and liposomal accumulation varied in the SK‐OV‐3 group, we individually obtained SPECT/CT images of SK‐OV‐3‐bearing mouse (n = 11) before Doxil^® treatment. Clear correlation between liposomal tumor accumulation and effects of Doxil^® was confirmed (R² = 0.73). Taken together, our experiments definitely verified that enhanced therapeutic effects through liposomal formulations of anticancer agents depend on tumor accumulation of liposomes. Tumor accumulation of the radiolabeled liposomes evaluated by SPECT/CT imaging is applicable to appropriately determine indications for liposomal antitumor agents.     

Lysophosphatidic acid‐induced expression of periostin in stromal cells: Prognoistic relevance of periostin expression in epithelial ovarian cancer

Lysophosphatidic acid (LPA) is a bioactive lipid crucial for the initiation and progression of ovarian cancer. Identification of LPA‐induced biomarkers is necessary for predicting prognosis of ovarian cancer patients. Here we report periostin, an extracellular matrix protein, as an LPA‐induced protein in stromal cells and as a prognostic marker in patients with epithelial ovarian cancer (EOC). In human EOC tissues, periostin was mainly expressed in cancer‐associated stromal fibroblasts, but not in cancer cells. The expression levels of periostin highly correlated with poor survival and tumor recurrence of ovarian cancer patients. Treatment of human adipose tissue‐derived stromal cells with LPA or conditioned media from human ovarian adenocarcinoma cell lines, such as SK‐OV‐3 and OVCAR‐3, induced expression of periostin. The periostin expression induced by cancer‐conditioned media was abrogated by silencing of the LPA receptor 1 expression using small hairpin RNA lentivirus. Recombinant periostin stimulated adhesion and invasion of SK‐OV‐3 human ovarian adenocarcinoma cells and induced expression of matrix metalloprotease‐2 in the cancer cells. These results suggest that LPA is associated with the expression of periostin in cancer‐associated fibroblasts of EOC.     

Treatment of pancreatic cancer using an oncolytic virus harboring the lipocalin‐2 gene

BACKGROUND:

The 5‐year survival rate for patients with pancreatic cancer is <5%, and it is always resistant to the current chemoradiotherapy. Therefore, new, effective agents for the treatment of pancreatic cancer are urgently needed. The promising strategy of cancer‐targeting gene virotherapy (CTGVT) has demonstrated great anticancer potential. The objective of the current study was to determine whether 1 CTGVT approach, oncolytic virus (OV)‐harboring lipocalin‐2, is capable of treating pancreatic cancer.

METHODS:

Tissue microarrays were constructed to detect the expression of lipocalin‐2 in 60 specimens of pancreatic adenocarcinoma. The clinical significance of lipocalin‐2 was investigated in an analysis of correlations between lipocalin‐2 expression and matched clinical characteristics. A lipocalin‐2–expressing OV, ZD55‐lipocalin‐2, was constructed by deleting the adenoviral protein E1B55kD. The antitumor efficacy and mechanisms of the OV were investigated in pancreatic cancer cells with v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in vitro and in vivo.

RESULTS:

Lipocalin‐2 expression was correlated with a good prognosis in patients with pancreatic adenocarcinoma. ZD55‐lipocalin‐2 dramatically inhibited the growth of pancreatic cancer in vitro and in vivo by inducing cytolysis and caspase‐dependent apoptosis.

CONCLUSIONS:

Higher lipocalin‐2 expression predicted a better prognosis in patients with pancreatic cancer. The results indicated that ZD55‐lipocalin‐2, which specifically expressed higher levels of lipocalin‐2 in tumor cells, may serve as a potent anticancer drug for pancreatic cancer therapy, especially for patients who have pancreatic adenocarcinoma with KRAS mutations. Cancer 2012. © 2012 American Cancer Society.     

Secreted factors from metastatic prostate cancer cells stimulate mesenchymal stem cell transition to a pro‐tumourigenic ‘activated’ state that enhances prostate cancer cell migration

Mesenchymal stem cells (MSCs) are a heterogeneous population of multipotent cells that are capable of differentiating into osteocytes, chondrocytes and adipocytes. Recently, MSCs have been found to home to the tumour site and engraft in the tumour stroma. However, it is not yet known whether they have a tumour promoting or suppressive function. We investigated the interaction between prostate cancer cell lines 22Rv1, DU145 and PC3, and bone marrow‐derived MSCs. MSCs were ‘educated’ for extended periods in prostate cancer cell conditioned media and PC3‐educated MSCs were found to be the most responsive with a secretory profile rich in pro‐inflammatory cytokines. PC3‐educated MSCs secreted increased osteopontin (OPN), interleukin‐8 (IL‐8) and fibroblast growth factor‐2 (FGF‐2) and decreased soluble fms‐like tyrosine kinase‐1 (sFlt‐1) compared to untreated MSCs. PC3‐educated MSCs showed a reduced migration and proliferation capacity that was dependent on exposure to PC3‐conditioned medium. Vimentin and α‐smooth muscle actin (αSMA) expression was decreased in PC3‐educated MSCs compared to untreated MSCs. PC3 and DU145 education of healthy donor and prostate cancer patient‐derived MSCs led to a reduced proportion of FAP+ αSMA+ cells contrary to characteristics commonly associated with cancer associated fibroblasts (CAFs). The migration of PC3 cells was increased toward both PC3‐educated and DU145‐educated MSCs compared to untreated MSCs, while DU145 migration was only enhanced toward patient‐derived MSCs. In summary, MSCs developed an altered phenotype in response to prostate cancer conditioned medium which resulted in increased secretion of pro‐inflammatory cytokines, modified functional activity and the chemoattraction of prostate cancer cells.     

Successful treatment of refractory metastatic histiocytic sarcoma with alemtuzumab

BACKGROUND:

Histiocytic sarcoma (HS) is an exceedingly rare tumor and carries a dismal prognosis when patients present with advanced‐stage disease. Because of the poor response rates to conventional chemotherapy and the rarity of the disease, no standard of care exists for patients with HS. The authors report the single‐agent use of the anti‐CD52 antibody alemtuzumab in 2 patients who had advanced‐stage HS.

METHODS:

Two patients with chemotherapy‐refractory, metastatic HS with tumors that expressed the CD52 antigen received a prolonged course of treatment with the anti‐CD52 monoclonal antibody alemtuzumab.

RESULTS:

Resected tumor samples from both patients demonstrated CD52 expression. Both patients had marked responses to single‐agent alemtuzumab. One patient had a complete response with no evidence of disease for >5 years. The second patient had a major response to alemtuzumab and also remained alive with no evidence of disease for >4 years.

CONCLUSIONS:

Further studies need to be performed to examine CD52 expression and function in HS as well as the role of alemtuzumab in a larger cohort of patients. However, the clinical impact of single‐agent alemtuzumab in the 2 patients described in this report was very encouraging. Given the toxicity and frequent inefficacy of conventional chemotherapy, patients with incompletely resected HS should be strongly considered for alemtuzumab therapy. Cancer 2012. © 2011 American Cancer Society.     

Improved survival for fallopian tube cancer

BACKGROUND.

Fallopian tube cancers are rare neoplasms. These malignancies are thought to behave biologically and clinically like ovarian cancer. The purpose of this study was to compare the clinical behavior and outcome of fallopian tube and ovarian cancer.

METHODS.

The Surveillance, Epidemiology, and End Results database was reviewed to identify women with tumors of the fallopian tube (FT) and ovary (OV) diagnosed between 1988 and 2004. Demographic and clinical data were compared, and the impact of tumor site on survival was analyzed using Cox models and the Kaplan‐Meier method.

RESULTS.

A total of 55,825 patients were identified, 1576 (3%) with FT and 54,249 (97%) with OV cancer. FT patients were more likely to present with early stage tumors (P < .001). Among FT patients, 47% had stage I/II tumors compared with 29% of OV cancers. In an adjusted Cox model of all patients, cancer‐specific mortality was 48% lower in FT patients (hazard ratio, 0.52; 95% confidence interval [CI], 0.48‐0.56) compared with OV cancer. Among patients with FT tumors, advanced age and stage were independent predictors of decreased survival. When stratified by stage, survival was similar for stage I and II tumors, but stage III and IV FT patients had an improved survival. The 5‐year survival for stage III FT cancer was 54% (95% CI, 48%‐60%), compared with 30% (95% CI, 29%‐31%) for OV.

CONCLUSIONS.

Fallopian tube cancers present earlier and at advanced stage have a better overall survival than primary ovarian malignancies. Future clinical trials should recognize the possible distinct clinical behavior of fallopian tube cancers. Cancer 2008. © 2008 American Cancer Society.     

Inhibitory effect and mechanism of mesenchymal stem cells on melanoma cells

Purpose

To explore the inhibitory effect and mechanism of MSCs on melanoma proliferation.

Methods

The inhibitory effect of MSCs on melanoma A375 cells was detected by co-culture and conditioned medium (CM) experiments using MTT method. The cell cycle was analyzed by flow cytometry. Then, Western Blot experiment detected the expression of proteins related to NF-κB signaling in A375 cells. The expression of IL-1Ra in MSCs was proved by RT-PCR. The over-expression and silencing vector pcDNA3.1-EGFP-IL-1Ra and pGPH1-IL-1R were constructed and transfected into MSCs cells. After that, the changes of inhibitory effect and cell cycle from MSCs-S and MSCs-O CM on A375 cells were explored. The expression of proteins related to NF-κB signaling in A375 cells after MSCs-S or MSCs-O CM treatment was detected by Western Blot. MSCs, MSCs-S, or MSCs-O and A375 cells were co-injected into nude mice under the arms, the growth of tumor was observed, the frozen sections were made, and H&E staining of tumor tissue was performed.

Results

The proliferation of A375 cells was inhibited and the cell cycle of A375 was arrested by MSCs. The expressions of cytokines related to NF-κB signaling were down-regulated. Over-expression and silence of Interleukin 1 receptor antagonist (IL-1Ra), specifically blocking activation of NF-κB signaling, indicated that inhibitory effect from MSCs was enhanced or weakened respectively, which suggested that IL-1Ra was involved in the inhibitory effect. In vivo, tumor initiation and growth were significantly inhibited when A375 cells were co-injected with MSCs into nude mice, which were related to the expression level of IL-1Ra.

Conclusion

MSCs could inhibit the proliferation and tumor initiation of melanoma A375 cells through NF-κB signaling. MSCs could secret IL-1Ra and inhibit expressions of NF-κB signaling-related factors of tumor cells, and cause cell cycle arrest in G1 phase.

     

CD90+ stromal cells are the major source of IL‐6, which supports cancer stem‐like cells and inflammation in colorectal cancer

IL‐6 is a pleiotropic cytokine increased in CRC and known to directly promote tumor growth. Colonic myofibroblasts/fibroblasts (CMFs or stromal cells) are CD90⁺ innate immune cells representing up to 30% of normal colonic mucosal lamina propria cells. They are expanded in CRC tumor stroma, where they also known as a cancer associated fibroblasts (CAFs). Cells of mesenchymal origin, such as normal myofibroblasts/fibroblasts, are known to secrete IL‐6; however, their contribution to the increase in IL‐6 in CRC and to tumor‐promoting inflammation is not well defined. Using in situ, ex vivo and coculture analyses we have demonstrated that the number of IL‐6 producing CMFs is increased in CRC (C‐CMFs) and they represent the major source of IL‐6 in T2‐T3 CRC tumors. Activity/expression of stem cell markers‐aldehyde dehydrogenase and LGR5‐ was significantly up‐regulated in colon cancer cells (SW480, Caco‐2 or HT29) cultured in the presence of conditioned medium from tumor isolated C‐CMFs in an IL‐6 dependent manner. C‐CMF and its derived condition medium, but not normal CMF isolated from syngeneic normal colons, induced differentiation of tumor promoting inflammatory T helper 17 cells (Th17) cell responses in an IL‐6 dependent manner. Our study suggests that CD90⁺ fibroblasts/myofibroblasts may be the major source of IL‐6 in T2‐T3 CRC tumors, which supports the stemness of tumor cells and induces an immune adaptive inflammatory response (a.k.a. Th17) favoring tumor growth. Taken together our data supports the notion that IL‐6 producing CAFs (a.k.a. C‐CMFs) may provide a useful target for treating or preventing CRCs.     

Breast carcinoma cells modulate the chemoattractive activity of human bone marrow‐derived mesenchymal stromal cells by interfering with CXCL12

We investigated whether breast tumor cells can modulate the function of mesenchymal stromal cells (MSCs) with a special emphasis on their chemoattractive activity towards hematopoietic stem and progenitor cells (HSPCs). Primary MSCs as well as a MSC line (SCP‐1) were cocultured with primary breast cancer cells, MCF‐7, MDA‐MB231 breast carcinoma or MCF‐10A non‐malignant breast epithelial cells or their conditioned medium. In addition, the frequency of circulating clonogenic hematopoietic progenitors was determined in 78 patients with breast cancer and compared with healthy controls. Gene expression analysis of SCP‐1 cells cultured with MCF‐7 medium revealed CXCL12 (SDF‐1) as one of the most significantly downregulated genes. Supernatant from both MCF‐7 and MDA‐MB231 reduced the CXCL12 promoter activity in SCP‐1 cells to 77% and 47%, respectively. Moreover, the CXCL12 mRNA and protein levels were significantly reduced. As functional consequence of lower CXCL12 levels, we detected a decreased trans‐well migration of HSPCs towards MSC/tumor cell cocultures or conditioned medium. The specificity of this effect was confirmed by blocking studies with the CXCR4 antagonist AMD3100. Downregulation of SP1 and increased miR‐23a levels in MSCs after contact with tumor cell medium as well as enhanced TGFβ1 expression were identified as potential molecular regulators of CXCL12 activity in MSCs. Moreover, we observed a significantly higher frequency of circulating colony‐forming hematopoietic progenitors in patients with breast cancer compared with healthy controls. Our in vitro results propose a potential new mechanism by which disseminated tumor cells in the bone marrow may interfere with hematopoiesis by modulating CXCL12 in protected niches.     

Expression of the stem cell marker CD133 in recurrent glioblastoma and its value for prognosis

BACKGROUND:

Experimental data suggest that glioblastoma cells expressing the stem cell marker CD133 play a major role in radiochemoresistance and tumor aggressiveness. To date, however, there is no clinical evidence that the fraction of CD133‐positive cells in glioblastoma that recurs after radiochemotherapy may be relevant for prognosis.

METHODS:

The authors used immunohistochemistry to assess CD133 expression in 37 paired glioblastoma samples, including 1 primary tumor sample and 1 recurrent tumor sample, after patients received adjuvant radiochemotherapy. To assess the actual composition of the CD133‐positive glioblastoma cell population, fluorescence‐associated cell sorting (FACS) analysis was used to sort CD133‐positive/CD45‐negative cells that were assayed for tumor‐specific chromosomal aberrations using interphase fluorescence in situ hybridization. To rule out endothelial precursor cells, CD133‐positive fractions also were assayed with anti‐CD34 by FACS.

RESULTS:

In recurrent glioblastomas, the percentage of CD133‐positive cells was increased by 4.6‐fold compared with the percentage in primary glioblastomas, although, in some tumors, it increased up to 10‐fold and 20‐fold. Unexpectedly, the increase in CD133 expression was associated significantly with longer survival after tumor recurrence. An analysis of tumor‐specific chromosomal aberrations and in vivo studies revealed that the CD133‐positive cell compartment of recurrent glioblastoma was composed of both cancer stem cells and nontumor neural stem cells. The latter cells represented from 20% to 60% of the CD133‐positive cell population, and their relative percentage favorably affected the survival of patients with recurrent glioblastoma. Endothelial CD133‐positive/CD34‐positive precursors did not contribute to the CD133‐positive cell population.

CONCLUSIONS:

The authors hypothesized that, similar to the phenomenon described in glioblastoma models, neural stem/progenitor cells that are recruited by the tumor from surrounding brain may exert an antitumorigenic effect. Cancer 2011. © 2010 American Cancer Society.     

Mesenchymal Stem Cells Promote Pancreatic Tumor Growth by Inducing Alternative Polarization of Macrophages

Pancreatic cancer is characterized by an extensive desmoplastic stroma, the functional relevance of which is poorly understood. Activated fibroblasts are a prevalent component of the stroma, and traditionally, these cells have been considered as a homogenous population derived from pancreatic stellate cells. In this study, we highlight a previously unappreciated heterogeneity of the fibroblast population within the stroma. In particular, a subset of stromal fibroblasts has characteristics of mesenchymal stem cells (MSCs). MSCs are present in the normal pancreas as well as in the carcinomatous pancreas (CA-MSCs). Here, we determine that CA-MSCs have increased tumor-promoting function compared with MSCs in normal pancreas. This ability to promote tumor growth is associated with CA-MSCs’ unique ability to promote alternative macrophage polarization. Thus, our study identifies a previously uncharacterized cell population within the stroma and sheds light on tumor-promoting interactions between different components of the stroma.

Significance

Targeting the stroma is emerging as a new paradigm in pancreatic cancer; however, efforts to that effect are hampered by our limited understanding of the nature and function of stromal components. Here, we uncover previously unappreciated heterogeneity within the stroma and identify interactions among stromal components that promote tumor growth and could be targeted therapeutically.     

Predictors of distress in female breast cancer survivors: a systematic review

Purpose

Breast cancers have a poorer prognosis if estrogen receptor expression was lost during recurrence. It is unclear whether this conversion is cell autonomous or whether it can be promoted by the microenvironment during cancer dormancy. We explored the ability of marrow-derived stromal cell lines to arrest co-cultured breast cancer cells and suppress estrogen receptor alpha (ER) expression during arrest, facilitating the emergence of estrogen-independent breast cancer clones.

Methods

Cancer cell growth, ER protein, microRNA, and mRNA levels were measured in breast cancer cell lines exposed to conditioned medium from marrow stromal lines in the presence and absence of estrogen and of signaling pathway modulators.

Results

We demonstrate that paracrine signaling from the stromal cell line HS5 downregulated ER in T47D and MCF7 breast cancer cells. This occurred at the mRNA level and also through decreased ER protein stability. Additionally, conditioned medium (CM) from HS5 arrested the breast cancer cells in G0/G1 in part through interleukin-1 (IL1) and inhibited cancer cell growth despite the activation of proliferative pathways (Erk and AKT) by the CM. Similar findings were observed for CM from the hFOB 1.19 osteoblastic cell line but not from two other fibroblastic marrow lines, HS27A and KM101. HS5-CM inhibition of MCF7 proliferation could not be restored by exogenous ER, but was restored by the IL1-antagonist IL1RA. In the presence of IL1RA, HS5-CM activation of AKT and Erk enabled the outgrowth of breast cancer cells with suppressed ER that were fulvestrant-resistant and estrogen-independent.

Conclusions

We conclude that marrow-derived stromal cells can destabilize estrogen receptor protein to convert the ER status of growth-arrested ER+ breast cancer cell lines. The balance between stromal pro- and anti-proliferative signals controlled the switch from a dormant phenotype to estrogen-independent cancer cell growth.

     

Correlation of [18F]‐2‐fluoro‐deoxy‐D‐glucose positron emission tomography standard uptake values with the cellular composition of stage I nonsmall cell lung cancer

BACKGROUND:

The aim of the current study was to determine whether the [18F]‐2‐fluoro‐deoxy‐D‐glucose (FDG) positron emission tomography (PET) standardized uptake value (SUV) in patients with a new diagnosis of stage I lung cancer correlates with a specific cellular component in the primary tumor.

METHODS:

This study was Health Insurance Portability and Accountability Act compliant and approved by our Institutional Review Board with a waiver of informed consent. Forty patients with stage I nonsmall cell lung cancer (NSCLC) who underwent FDG‐PET imaging at the time of diagnosis followed by surgical resection were retrospectively identified. Histologic sections of the primary tumor were reviewed by a pathologist without any clinical data and scored according to the percentage of each cellular component (tumor cells, normal stroma, inflammatory cells, necrosis, fibrosis, and other). Each component was compared with maximal (SUV_max) and mean (SUV_mean) SUVs using Pearson correlation coefficient analysis.

RESULTS:

The mean SUV_max and SUV_mean values for 40 stage I NSCLC tumors were 8.8 and 5.4, respectively. The mean histologic composition of tumor specimens in order of frequency was as follows: tumor cells (38.9%), fibrosis (30.8%), inflammatory cells (14.8%), normal stroma (5.2%), necrosis (5.8%), and other components (4.5%); however, there was considerable variation noted among individual tumors. There was no statistically significant correlation between SUV_max (r = .19; P = .24) or SUV_mean (r = .017; P = .29) and the proportion of tumor cells in the tumor mass or any other cellular components.

CONCLUSIONS:

The cellular composition of stage I NSCLC appears to be highly variable, with no correlation noted between a specific tumor cellular component and FDG activity. Cancer 2010. © 2010 American Cancer Society.     

Prognostic impact of extracellular matrix metalloprotease inducer

BACKGROUND:

Extracellular matrix metalloprotease inducer (EMMPRIN) induces matrix metalloproteinase (MMP) expression, tumor‐stroma cell interaction, and invasion/angiogenesis. The objectives of the current study were to find the first evidence of a prognostic impact of total and relative EMMPRIN expression in colorectal cancer cells and to analyze EMMPRIN in bone marrow‐disseminated tumor cells and normal cells from 2 different gastrointestinal cancer entities.

METHODS:

Tumors and normal tissues from 40 patients with colorectal cancer who were followed prospectively (median follow‐up, 31 months) were analyzed for EMMPRIN by immunohistochemistry. Bone marrow from 51 patients (13 patients with gastric cancer and 38 patients with colorectal cancer) with evidence of disseminated tumor cells was screened for EMMPRIN in tumor cells and normal cells (cytokeratin 18/EMMPRIN double immunocytochemistry).

RESULTS:

A significant correlation between poor disease‐specific survival (P = .037; Kaplan‐Meier method; Mantel‐Cox log‐rank tests) and an increased ratio of EMMPRIN in tumor cells versus corresponding normal epithelial cells were observed. Furthermore, the relative increase of EMMPRIN was associated with a trend toward poor overall and recurrence‐free survival. High relative EMMPRIN expression was associated significantly with positive metastasis status (M1) (P = .001) and with a trend towards advanced pathologic tumor classification. Sixteen percent of disseminated tumor cells in bone marrow samples from patients with colorectal cancer and 48.5% of disseminated tumor cells in bone marrow samples from patients with gastric cancer stained positive for EMMPRIN, and EMMPRIN on micrometastatic cells was associated significantly with parameters of tumor progression (M status, noncurative resectability). A minority of normal bone marrow cells were stained for EMMPRIN, suggesting their suitability for molecular targeting.

CONCLUSIONS:

To the authors' knowledge, this study was the first to indicate that increased relative EMMPRIN protein in tumor‐specific cells compared with normal cells predicts poor disease‐specific survival in patients with colorectal cancer and that EMMPRIN in primary and bone marrow‐disseminated tumor cells is associated with clinical markers of tumor progression in patients with colorectal/gastric cancer. Cancer 2009. © 2009 American Cancer Society.