Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.

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Microenvironmental regulation of tumor progression and metastasis.

Blood vessels constitute the first organ in the embryo and form the largest network in our body but, sadly, are also often deadly. When dysregulated, the formation of new blood vessels contributes to numerous malignant, ischemic, inflammatory, infectious and immune disorders. Molecular insights into these processes are being generated at a rapidly increasing pace, offering new therapeutic opportunities that are currently being evaluated.

Angiogenesis in health and disease.

Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen in vitro and an angiogenic inducer in a variety of in vivo models. Hypoxia has been shown to be a major inducer of VEGF gene transcription. The tyrosine kinases Flt-1 (VEGFR-1) and Flk-1/KDR (VEGFR-2) are high-affinity VEGF receptors. The role of VEGF in developmental angiogenesis is emphasized by the finding that loss of a single VEGF allele results in defective vascularization and early embryonic lethality. VEGF is critical also for reproductive and bone angiogenesis. Substantial evidence also implicates VEGF as a mediator of pathological angiogenesis. In situ hybridization studies demonstrate expression of VEGF mRNA in the majority of human tumors. Anti-VEGF monoclonal antibodies and other VEGF inhibitors block the growth of several tumor cell lines in nude mice. Clinical trials with various VEGF inhibitors in a variety of malignancies are ongoing. Very recently, an anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the Food and Drug Administration as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy. Furthermore, VEGF is implicated in intraocular neovascularization associated with diabetic retinopathy and age-related macular degeneration.

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Vascular endothelial growth factor: basic science and clinical progress.

Stromal Fibroblasts Present in Invasive Human Breast Carcinomas Promote Tumor Growth and Angiogenesis through Elevated SDF-1/CXCL12 Secretion

The role of bone marrow (BM)-derived precursor cells in tumor angiogenesis is not known. We demonstrate here that tumor angiogenesis is associated with recruitment of hematopoietic and circulating endothelial precursor cells (CEPs). We used the angiogenic defective, tumor resistant Id-mutant mice to show that transplantation of wild-type BM or vascular endothelial growth factor (VEGF)-mobilized stem cells restore tumor angiogenesis and growth. We detected donor-derived CEPs throughout the neovessels of tumors and Matrigel-plugs in an Id1+/-Id3-/- host, which were associated with VEGF-receptor-1-positive (VEGFR1+) myeloid cells. The angiogenic defect in Id-mutant mice was due to impaired VEGF-driven mobilization of VEGFR2+ CEPs and impaired proliferation and incorporation of VEGFR1+ cells. Although targeting of either VEGFR1 or VEGFR2 alone partially blocks the growth of tumors, inhibition of both VEGFR1 and VEGFR2 was necessary to completely ablate tumor growth. These data demonstrate that recruitment of VEGF-responsive BM-derived precursors is necessary and sufficient for tumor angiogenesis and suggest new clinical strategies to block tumor growth.

Impaired recruitment of bone-marrow–derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth

The cytolytic activity of NK cells is tightly regulated by inhibitory receptors specific for MHC class I Ags. We have investigated the composition of signal transduction molecules in the supramolecular activation clusters in the MHC class I-regulated cytolytic and noncytolytic NK cell immune synapses. KIR2DL3-positive NK clones that are specifically inhibited in their cytotoxicity by HLA-Cw*0304 and polyclonal human NK cells were used for conjugate formation with target cells that are either protected or are susceptible to NK cell-mediated cytotoxicity. Polarization of talin, microtubule-organizing center, and lysosomes occurred only during cytolytic interactions. The NK immune synapses were analyzed by three-dimensional immunofluorescence microscopy, which showed two distinctly different synaptic organizations in NK cells during cytolytic and noncytolytic interactions. The center of a cytolytic synapse with MHC class I-deficient target is comprised of a complex of signaling molecules including Src homology (SH)2-containing protein tyrosine phosphatase-1 (SHP-1). Closely related molecules with overlapping functions, such as the Syk kinases, SYK, and ZAP-70, and adaptor molecules, SH2 domain-containing leukocyte protein of 76 kDa and B cell linker protein, are expressed in activated NK cells and are all recruited to the center of the cytolytic synapse. In contrast, the noncytolytic synapse contains SHP-1, but is lacking other components of the central supramolecular activation cluster. These findings indicate a functional role for SHP-1 in both the cytolytic and noncytolytic interactions. We also demonstrate, in three-cell conjugates, that a single NK cell forms a cytolytic synapse with a susceptible target cell in the presence of both susceptible and nonsusceptible target cells.

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Spatial organization of signal transduction molecules in the NK cell immune synapses during MHC class I-regulated noncytolytic and cytolytic interactions.

Objective. To assess the degree, cause, and consequence of delays from presenting signs to diagnosis of retinoblastoma. Methods. A retrospective chart review was conducted of 64 consecutive patients who presented to the Memorial Sloan-Kettering Cancer Center with newly diagnosed retinoblastoma. Seven patients with a positive family history were excluded. Results. The median times from presenting signs to diagnosis for patients with unilateral and bilateral disease were 1.5 and 2.25 months (range: 0–46), respectively; for those who presented with leukocoria and strabismus, median times were 1.5 (range: 0–46) and 2.5 months (range: 0–24). Parents noted the first signs in 75% of the cases. Seventy-seven percent delayed seeking treatment, and primary care physicians (PCPs) delayed referral in 30%. Only 3 patients were referred from PCPs solely for physical examination findings. No adverse consequence of delayed diagnosis could be established clearly, but a trend toward eye loss being associated with longer delays in patients with bilateral retinoblastoma was noted. Conclusion. Leukocoria and strabismus secondary to retinoblastoma are usually first recognized by relatives rather than PCPs. At routine visits, PCPs should inform parents about the importance of reporting eye abnormalities, and children whose parents complain of leukocoria (white, shiny, jello-like eye) should be referred promptly to an ophthalmologist regardless of whether an absent red reflex is appreciated.

https://pediatrics.aappublications.org/content/pediatrics/109/3/e45.full.pdf

Delayed diagnosis of retinoblastoma: analysis of degree, cause, and potential consequences.

. Objective. To assess the degree, cause,and consequence of delays from presenting signs to di-agnosis of retinoblastoma. Methods. A retrospective chart review was conductedof 64 consecutive patients who presented to the Memo-rial Sloan-Kettering Cancer Center with newly diag-nosed retinoblastoma. Seven patients with a positivefamily history were excluded. Results. The median times from presenting signs todiagnosis for patients with unilateral and bilateral dis-ease were 1.5 and 2.25 months (range: 0–46), respectively;for those who presented with leukocoria and strabismus,median times were 1.5 (range: 0–46) and 2.5 months(range: 0–24). Parents noted the first signs in 75% of thecases. Seventy-seven percent delayed seeking treatment,and primary care physicians (PCPs) delayed referral in30%. Only 3 patients were referred from PCPs solely forphysical examination findings. No adverse consequenceof delayed diagnosis could be established clearly, but atrend toward eye loss being associated with longer de-lays in patients with bilateral retinoblastoma was noted.

Linda J. Butros

Papers

Impaired recruitment of bone-marrow–derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth

Spatial organization of signal transduction molecules in the NK cell immune synapses during MHC class I-regulated noncytolytic and cytolytic interactions.

Delayed diagnosis of retinoblastoma: analysis of degree, cause, and potential consequences.

Consequences Delayed Diagnosis of Retinoblastoma: Analysis of Degree, Cause, and Potential