Tumor stroma derived biomarkers in cancer

Sund, Malin; Kalluri, Raghu

doi:10.1007/s10555-008-9175-2

Cited by 130 publications

(109 citation statements)

References 52 publications

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“…The role of the TME in tumor progression and metastasis supports the approach of targeting one or more TME components for cancer therapeutics (7,15,50). HA in the TME is a promising target for cancer therapeutics due to its role in creating high intratumoral pressure resulting in blood vessel compression and development of hypoxia, epithelial-mesenchymal transition, tumor progression and metastasis, multidrug resistance, and tumor-bearing mice were dosed with NK-PKH26 cells (5 Â 10 6 ), trastuzumab (0.75 mg/kg) and AE PEGPH20 (40 mg/kg), and tumors were harvested at indicated time points for ex vivo imaging under the same exposure condition.…”

Section: Discussionmentioning

confidence: 97%

Tumor-Associated Hyaluronan Limits Efficacy of Monoclonal Antibody Therapy

Singha

Nekoroski

Zhao

et al. 2015

Molecular Cancer Therapeutics

116

101

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Despite tremendous progress in cancer immunotherapy for solid tumors, clinical success of monoclonal antibody (mAb) therapy is often limited by poorly understood mechanisms associated with the tumor microenvironment (TME). Accumulation of hyaluronan (HA), a major component of the TME, occurs in many solid tumor types, and is associated with poor prognosis and treatment resistance in multiple malignancies. In this study, we describe that a physical barrier associated with high levels of HA (HA high ) in the TME restricts antibody and immune cell access to tumors, suggesting a novel mechanism of in vivo resistance to mAb therapy. We determined that approximately 60% of HER2 3þ primary breast tumors and approximately 40% of EGFR þ head and neck squamous cell carcinomas are HA high , and hypothesized that HA high tumors may be refractory to mAb therapy. We found that the pericellular matrix produced by HA high tumor cells inhibited both natural killer (NK) immune cell access to tumor cells and antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. Depletion of HA by PEGPH20, a pegylated recombinant human PH20 hyaluronidase, resulted in increased NK cell access to HA high tumor cells, and greatly enhanced trastuzumab-or cetuximab-dependent ADCC in vitro. Furthermore, PEGPH20 treatment enhanced trastuzumab and NK cell access to HA high tumors, resulting in enhanced trastuzumab-and NK cell-mediated tumor growth inhibition in vivo. These results suggest that HA high matrix in vivo may form a barrier inhibiting access of both mAb and NK cells, and that PEGPH20 treatment in combination with anticancer mAbs may be an effective adjunctive therapy for HA high tumors.

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Section: Discussionmentioning

confidence: 97%

Tumor-Associated Hyaluronan Limits Efficacy of Monoclonal Antibody Therapy

Singha

Nekoroski

Zhao

et al. 2015

Molecular Cancer Therapeutics

116

101

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“…MAPK 14 (p38;ref. 33), urokinase plasminogen activator (uPA) protease (34), collagen 18 (35), and laminin 5 (36) derivatives can remodel node stroma to permit basement membrane invasion by tumor cells, while G-a13 signaling is required for vascular organization during these processes (37).…”

Section: Discussionmentioning

confidence: 99%

Exosomes Released by Melanoma Cells Prepare Sentinel Lymph Nodes for Tumor Metastasis

Hood¹,

San²,

Wickline³

2011

Cancer Research

887

747

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Exosomes are naturally occurring biological nanovesicles utilized by tumors to communicate signals to local and remote cells and tissues. Melanoma exosomes can incite a proangiogenic signaling program capable of remodeling tissue matrices. In this study, we show exosome-mediated conditioning of lymph nodes and define microanatomic responses that license metastasis of melanoma cells. Homing of melanoma exosomes to sentinel lymph nodes imposes synchronized molecular signals that effect melanoma cell recruitment, extracellular matrix deposition, and vascular proliferation in the lymph nodes. Our findings highlight the pathophysiologic role and mechanisms of an exosome-mediated process of microanatomic niche preparation that facilitates lymphatic metastasis by cancer cells. Cancer Res; 71(11); 3792-801. Ó2011 AACR.

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“…Therefore, CAFs play an important role in both tumor progression and regulation of the tumor microenvironment. Certain studies have suggested that in colorectal cancer, CAFs are associated with poor prognosis and distant metastasis (4,5,24). However, the evaluation of FAP-α and SDF-1 expression as CAF-associated markers and the association of their expression with clinicopathological variables in rectal cancer after CRT, have not been previously reported.…”

Section: Discussionmentioning

confidence: 99%

“…Over the years, the importance of the cancer stroma surrounding the tumor in the proliferation, invasion and metastasis of cancer cells has been increasingly recognized (4)(5)(6)(7). For example, Finak et al investigated stromal gene expression in primary breast cancer and constructed a stromaderived prognostic predictor, which was independent from all standard prognostic factors (8).…”

Section: Introductionmentioning

confidence: 99%

Cancer-associated fibroblasts correlate with poor prognosis in rectal cancer after chemoradiotherapy

Saigusa

Toiyama²,

Yokoe³

et al. 2011

Int J Oncol

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Abstract. Cancer-associated fibroblasts (CAFs) in the stroma play an important role in influencing the proliferation, invasion and metastasis of cancer cells. Fibroblast activation protein-α (FAP-α) is known as a marker of CAFs, while stromal cell-derived factor-1 (SDF-1) is primarily expressed by CAFs. Herein, we investigated whether the expression levels of these genes are associated with clinical outcome after pre-operative chemoradiotherapy (CRT) in rectal cancer patients. We obtained total RNA from residual cancer stroma using microdissection from a total of 52 rectal cancer specimens from patients who underwent pre-operative CRT, we performed transcriptional analyses, and the serum protein concentrations in 40 matched microdissected specimens were measured by enzyme-linked immunosorbent assay. Additionally, we sought to clarify the location of FAP-α and SDF-1 expression using immunohistochemical staining. Of the 52 patients, 15.6 and 36.8% showed detectable FAP-α and SDF-1 mRNA expression, respectively. A significant correlation was observed between stromal FAP-α and SDF-1 mRNA levels. Moreover, there was a significant correlation between stromal SDF-1 gene expression levels and serum protein levels. Patients who developed distant recurrences after CRT had positive expression of both genes (P<0.05). The positive expression of both genes was also associated with poor probability of recurrence-free and overall survival (P<0.05). Patients with elevated serum SDF-1 levels had equally poor overall survival as those with positive stromal SDF-1 gene expression (P<0.05). In immunohistochemistry, both FAP-α and SDF-1 expression was observed in certain activated fibroblasts. In conclusion, FAP-α and SDF-1 expression was shown to be involved in tumor re-growth and recurrence in rectal cancer patients treated with pre-operative CRT.

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Tumor stroma derived biomarkers in cancer

Cited by 130 publications

References 52 publications

Tumor-Associated Hyaluronan Limits Efficacy of Monoclonal Antibody Therapy

Tumor-Associated Hyaluronan Limits Efficacy of Monoclonal Antibody Therapy

Exosomes Released by Melanoma Cells Prepare Sentinel Lymph Nodes for Tumor Metastasis

Cancer-associated fibroblasts correlate with poor prognosis in rectal cancer after chemoradiotherapy

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