Collagen IV derived "tumstatin" suppresses tumor growth.

Collagen IV, the basement membrane collagen is probably one of the oldest and most examined subtypes of collagen in oncology.  It is certainly not the only or most important collagen in cancer suppression, or other diseases, but Col4 has been proven to function as a barrier against metastasis in the fibrous capsule in several sophisticated and technically up-to-date studies.

Inhibition of tumor angiogenesis by tumstatin: insights into signaling mechanisms and implications in cancer regression.

"Sudhakar A¹, Boosani CS.

Growing tumors develop additional new blood vessels to meet the demand for adequate nutrients and oxygen, a process called angiogenesis. Cancer is a highly complex disease promoted by excess angiogenesis; interfering with this process poses for an attractive approach for controlling tumor growth. This hypothesis led to the identification of endogenous angiogenesis inhibitors generated from type IV collagen, a major component of vascular basement membrane (VBM). Type IV collagen and the angiogenesis inhibitors derived from it are involved in complex roles, than just the molecular construction of basement membranes. Protease degradation of collagens in VBM occurs in various physiological and pathological conditions and produces several peptides. Some of these peptides are occupied in the regulation of functions conflicting from those of their original integral molecules. Tumstatin (alpha3(IV)NC1), a proteolytic C-terminal non-collagenous (NC1) domain from type IV collagen alpha3 chain has been highlighted recently because of its potential role in anti-angiogenesis, however its biological actions are not limited to these processes. alpha3(IV)NC1 inhibits proliferation by promoting endothelial cell apoptosis and suppresses diverse tumor angiogenesis, thus making it a potential candidate for future cancer therapy. The present review surveys the physiological functions of type IV collagen and discovery of alpha3(IV)NC1 as an antiangiogenic protein with a comprehensive overview of the knowledge gained by us towards understanding its signaling mechanisms."

Tumstatin, the NC1 domain of alpha3 chain of type IV collagen, is an endogenous inhibitor of pathological angiogenesis and suppresses tumor growth. 

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Hamano Y¹, Kalluri R.

Angiogenesis, the formation of new blood vessels, is required for physiological development of vertebrates and repair of damaged tissue, but in the pathological setting contributes to progression of cancer. During tumor growth, angiogenesis is supported by up-regulation of angiogenic stimulators (pro-angiogenic) and down-regulation of angiogenic inhibitors (anti-angiogenic). The switch to the angiogenic phenotype (angiogenic switch) allows the tumors to grow and facilitate metastasis. The bioactive NC1 domain of type IV collagen alpha3 chain, called tumstatin, imparts anti-tumor activity by inducing apoptosis of proliferating endothelial cells. Tumstatin binds to alphaVbeta3 integrin via a mechanism independent of the RGD-sequence recognition and inhibits cap-dependent protein synthesis in the proliferating endothelial cells. The physiological level of tumstatin is controlled by matrix metalloproteinase-9, which most effectively cleaves it from the basement membrane and its physiological concentration in the circulation keeps pathological angiogenesis and tumor growth in check. These findings suggest that tumstatin functions as an endogenous inhibitor of pathological angiogenesis and functions as a novel suppressor of proliferating endothelial cells and growth of tumors."

Collagen XIX is strongly anti-tumorigenic

The NC1 domain of type XIX collagen inhibits in vivo melanoma growth.

Mol Cancer Ther. 2007 Feb;6(2):506-14.

The NC1 domain of type XIX collagen inhibits in vivo melanoma growth.

Ramont L¹, Brassart-Pasco S, Thevenard J, Deshorgue A, Venteo L, Laronze JY, Pluot M, Monboisse JC, Maquart FX.

Type XIX collagen is a minor collagen that localizes to basement membrane zones, together with types IV, XV, and XVIII collagens. Because several NC1 COOH-terminal domains of other chains from basement membrane collagens were reported to exhibit antitumor activity, we decided to study the effects of the NC1(XIX) collagen domain on tumor progression using an experimental in vivo model of mouse melanoma. We observed a 70% reduction in tumor volume in NC1(XIX)-treated mice compared with the corresponding controls. Histologic examination of the tumors showed a strong decrease in tumor vascularization in treated mice. In vitro, NC1(XIX) inhibited the migrating capacity of tumor cells and their capacity to invade Matrigel. It also inhibited the capacity of human microvascular endothelial cells to form pseudotubes in Matrigel. This effect was accompanied by a strong inhibition of membrane type-1 matrix metalloproteinase (matrix metalloproteinase-14) and vascular endothelial growth factor expression. Collectively, our data indicate that the NC1 domain of type XIX collagen exerts antitumor activity. This effect is mediated by a strong inhibition of the invasive capacities of tumor cells and antiangiogenic effects. NC1(XIX) should now be considered as a new member of the basement membrane collagen-derived matrikine family with antitumor and antiangiogenic activity.

PMID: 17308049

 

The NC1 domain of type XIX collagen inhibits melanoma cell migration. 

Eur J Dermatol. 2010 Nov-Dec;20(6):712-8. doi: 10.1684/ejd.2010.1070. Epub 2010 Sep 14.
 The NC1 domain of type XIX collagen inhibits melanoma cell migration.

Toubal A¹, Ramont L, Terryn C, Brassart-Pasco S, Patigny D, Sapi J, Monboisse JC, Maquart FX.

Type XIX collagen is a minor collagen that localizes to basement membrane zones. We previously demonstrated that the C-terminal NC1 domain of type XIX collagen inhibits tumor growth in vivo. In the present study, we analyzed the effects of the NC1(XIX) collagen domain on migratory behaviour of melanoma B16F10 cells. We found that NC1(XIX) do not inhibit melanoma cell proliferation. On the contrary, NC1(XIX) strongly inhibited the migratory capacities of melanoma cells in the scratch wound model and in Ibidi® devices: cell migration speed was 7.69 ± 1.49 μm/h for the controls vs 6.64 ± 0.82 μm/h for cells incubated with 30 μmol/L NC1(XIX) and 5.72 ± 0.67 μmol/h with 60 μmol/L NC1(XIX). Similar results were obtained with UACC 903 human melanoma cells. Further work will be necessary to elucidate the molecular mechanisms of this migration inhibition. It may, however, explain, at least partially, the inhibition of tumor growth that we observed in vivo.

PMID: 20840910

 

 

Loss of Collagen XV Causes Muscle Tissue and Capillary Degeneration

Lack of type XV collagen causes a skeletal myopathy and cardiovascular defects in mice.

From:

Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1194-9. Epub 2001 Jan 23.

Lack of type XV collagen causes a skeletal myopathy and cardiovascular defects in mice.

Eklund L¹, Piuhola J, Komulainen J, Sormunen R, Ongvarrasopone C, Fássler R, Muona A, Ilves M, Ruskoaho H, Takala TE, Pihlajaniemi T.

Muscle histology: focal areas of degeneration, regeneration, and variation in fiber size. Hematoxylin and eosin-stained sections of the gastrocnemius (A), triceps brachii (B), paraspinal (C), and quadriceps (D) muscles of 6-month-old null mice showing cell degeneration (curved arrows, A and C) with macrophage infiltration (A), regenerative fibers (thin arrow, B), central nuclei (thin arrow, C), and increased variation in fiber size with atrophic muscle fibers (D, arrowheads) compared with age-matched wild-type mice (E). Original magnifications: A and D, ×300; B, ×200; C and E, ×80.

Ultrastructural changes in capillaries. Electron microscopy of heart capillaries from a wild-type (A) and a null mouse (B) with swollen endothelial cells (asterisks). The lumen is indicated by a white arrow. Skeletal muscle capillaries from a wild-type (C) and a mutant mouse (D) showing luminal narrowing and folding of endothelial cells.

Effect of isoproterenol stimulation on developed pressure in (A) 6-month-old and (B) 12-month-old mutant and wild-type mice. The responses to β-agonists were measured in terms of the ratio of the maximal value of the developed pressure (DP) to the basal level before the isoproterenol perfusion in Col15a1^−/− (●: A, n = 7; B, n = 11) and Col15a1^+/+ (□: A, n = 7; B, n = 8) mice. The symbols represent mean ± SEM. Significant differences between the Col15a1^−/− and Col15a1^+/+ mice are indicated by asterisks as follows: *, P < 0.05, **, P < 0.01. The basal pressure was 31.7 ± 5.0 and 27.3 ± 5.0 mmHg for the 6-month-old control and null mice, respectively, and 20.2 ± 3.4 and 20.8 ± 2.0 mmHg for the 1-year-old mice (mean ± SEM).