From 91baf196beaec6d14698964dfe3422adb53850d3 Mon Sep 17 00:00:00 2001 From: Modupe Date: Wed, 15 Jan 2025 15:45:16 -0600 Subject: [PATCH 1/6] ecc: introduces the vascular proliferation characteristic --- ecc/morph/ECC-MORPH-000001.yml | 59 ++++++++++++++++++++++++++++++++++ 1 file changed, 59 insertions(+) create mode 100644 ecc/morph/ECC-MORPH-000001.yml diff --git a/ecc/morph/ECC-MORPH-000001.yml b/ecc/morph/ECC-MORPH-000001.yml new file mode 100644 index 0000000..e0e86a3 --- /dev/null +++ b/ecc/morph/ECC-MORPH-000001.yml @@ -0,0 +1,59 @@ +state: proposed +name: Vascular Proliferation +identifier: ECC-MORPH-000001 +rfc: https://github.com/stjudecloud/ecc/issues/7 +assignment: morphological +description: | + Judah Folkman first discovered the concept of rapid blood vessel growth in 1971, as detailed in his publication in the *New England Journal of Medicine* (NEJM), referenced [here](https://pubmed.ncbi.nlm.nih.gov/4938153/). + His work laid the foundation for further research into angiogenesis, the process of forming new blood vessels. + +evaluation: | + - "Immunohistochemistry (IHC) of angiogenesis-related markers like CD34, VEGF, FVIII-RA, CD31, Ki-67." + - "H&E staining" + - qPCR to measure expression levels of angiopoietins and/or VEGF, https://pubmed.ncbi.nlm.nih.gov/10669954/, https://www.nature.com/articles/3780177 + +values: + kind: binary + description: + "true": + summary: Here is a summary for the 'true' value. + details: | + Here is a much longer description. + + This description is spread across multiple lines. It can be in paragraph + form and should be hardwrapped at 88 characters. + "false": + summary: Here is a summary for the 'false' value. + details: | + Here is a much longer description. + + This description is spread across multiple lines. It can be in paragraph + form and should be hardwrapped at 88 characters. +references: + - kind: manuscript + title: Vascular smooth muscle hyperplasia underlies the formation of glomeruloid vascular structures of glioblastoma multiforme + authors: + context: + url: https://pubmed.ncbi.nlm.nih.gov/1381413/ + highlighted: true + - kind: manuscript + title: Proliferative potential of vascular components in human glioblastoma multiforme + authors: + context: + url: https://pubmed.ncbi.nlm.nih.gov/3039783/ + highlighted: true + - kind: manuscript + title: Early and extensive contribution of pericytes/vascular smooth muscle cells to microvascular proliferation in glioblastoma multiforme: an immuno-light and immuno-electron microscopic study + authors: + context: + url: https://pubmed.ncbi.nlm.nih.gov/7745429/ + - kind: manuscript + title: Genetic modulation of hypoxia induced gene expression and angiogenesis: relevance to brain tumors + authors: + context: + url: https://pubmed.ncbi.nlm.nih.gov/12456339/ + - kind: manuscript + title: Angiogenesis and expression of PDGF-C, VEGF, CD105 and HIF-1α in human glioblastoma + authors: + context: + url: "https://pubmed.ncbi.nlm.nih.gov/24612214/" \ No newline at end of file From 6b00c312459f1936fccb36accd801b95b7501836 Mon Sep 17 00:00:00 2001 From: Modupe Date: Wed, 15 Jan 2025 16:22:03 -0600 Subject: [PATCH 2/6] ecc: updates vascular proliferation characteristic information --- ecc/morph/ECC-MORPH-000001.yml | 27 ++++++++++++++++----------- 1 file changed, 16 insertions(+), 11 deletions(-) diff --git a/ecc/morph/ECC-MORPH-000001.yml b/ecc/morph/ECC-MORPH-000001.yml index e0e86a3..97cf6e6 100644 --- a/ecc/morph/ECC-MORPH-000001.yml +++ b/ecc/morph/ECC-MORPH-000001.yml @@ -32,28 +32,33 @@ values: references: - kind: manuscript title: Vascular smooth muscle hyperplasia underlies the formation of glomeruloid vascular structures of glioblastoma multiforme - authors: - context: + authors: Haddad SF, Moore SA, Schelper RL, Goeken JA. + context: | + A study of seven glioblastomas with glomeruloid vascular structures suggests that these formations result primarily from smooth muscle hyperplasia. Endothelial cells of both normal and glomeruloid vessels stained positively for UEA-1 and factor VIII-related antigen (fVIII/RAg), while smooth muscle cells stained with muscle-specific actin antibodies (MSA and SMSA). The lack of MSA/SMSA staining in the endothelial cells of the glomeruloid structures indicates that smooth muscle cells, rather than endothelial cells, are primarily involved in the vascular proliferation seen in glioblastoma. url: https://pubmed.ncbi.nlm.nih.gov/1381413/ highlighted: true - kind: manuscript title: Proliferative potential of vascular components in human glioblastoma multiforme - authors: - context: + authors: Nagashima T, Hoshino T, Cho KG. + context: | + In a study of 16 glioblastoma multiforme patients, 5-bromo-deoxyuridine (BrdU) was used to label S-phase cells in tumor tissue. The BrdU labeling index (LI) for vascular components was significantly higher in glioblastomas than in normal brain tissue, but lower than the tumor cells themselves. Primary tumors had a higher vascular BrdU LI (4.5%) compared to recurrent tumors (2.7%), though the difference was not statistically significant. Vascular labeling was inconsistent, occurring mainly in glomerular-shaped vessels, with only 20% showing labeled cells. These findings suggest that vascular proliferation in glioblastomas may slow down or cease at a certain stage and is unlikely to be due to neoplastic transformation. url: https://pubmed.ncbi.nlm.nih.gov/3039783/ highlighted: true - kind: manuscript title: Early and extensive contribution of pericytes/vascular smooth muscle cells to microvascular proliferation in glioblastoma multiforme: an immuno-light and immuno-electron microscopic study - authors: - context: + authors: Wesseling P, Schlingemann RO, Rietveld FJ, Link M, Burger PC, Ruiter DJ + context: | + Recent studies of glioblastoma multiforme (GBM) microvascular proliferation (MVP) suggest that pericytes and vascular smooth muscle cells (VSMC), not just endothelial cells (EC), play a major role. Immunohistochemical analysis revealed two distinct cell types—EC and pericytes/VSMC—with no transitional forms. Pericytes/VSMC were found to contribute extensively to MVP, particularly in early stages of tumor capillary formation, highlighting their essential role in GBM angiogenesis. url: https://pubmed.ncbi.nlm.nih.gov/7745429/ - kind: manuscript - title: Genetic modulation of hypoxia induced gene expression and angiogenesis: relevance to brain tumors - authors: - context: + title: Genetic modulation of hypoxia induced gene expression and angiogenesis, relevance to brain tumors + authors: Brat DJ, Kaur B, Van Meir EG + context: | + Angiogenesis, crucial for the growth of infiltrative astrocytomas, manifests as "microvascular hyperplasia" in glioblastoma multiforme, the most aggressive form. This abnormal vascular proliferation, often linked to necrosis, is driven by hypoxic conditions within the tumor and genetic alterations. Hypoxia upregulates pro-angiogenic factors like VEGF through the HIF-1 pathway, which is influenced by genetic changes in oncogenes and tumor suppressor genes such as PTEN, TP53, and EGFR. These genetic alterations also impact the expression of other angiogenic factors, further promoting tumor angiogenesis. url: https://pubmed.ncbi.nlm.nih.gov/12456339/ - kind: manuscript title: Angiogenesis and expression of PDGF-C, VEGF, CD105 and HIF-1α in human glioblastoma - authors: - context: + authors: Clara CA, Marie SK, de Almeida JR, Wakamatsu A, Oba-Shinjo SM, Uno M, Neville M, Rosemberg S + context: | + This study analyzed the expression of PDGF-C, VEGF, and HIF-1α in 208 glioblastoma (GBM) cases to understand their role in angiogenesis and prognosis. The results showed that HIF-1α, VEGF, and PDGF-C were highly expressed in most tumors, with HIF-1α expression correlating with increased vascular density and higher VEGF and PDGF-C levels. A significant correlation was found between VEGF and PDGF-C expression in both tumor cells and blood vessels. Endothelial cells with positive VEGF and PDGF-C expression also showed markers of neoangiogenesis and proliferation. Nuclear staining for VEGF and HIF-1α was linked to poorer survival. The findings support the potential benefit of combined anti-angiogenic therapies for improving GBM treatment outcomes. url: "https://pubmed.ncbi.nlm.nih.gov/24612214/" \ No newline at end of file From 3915ae1709484a90cf09427dec37076571a57d32 Mon Sep 17 00:00:00 2001 From: Modupe Date: Wed, 15 Jan 2025 16:30:16 -0600 Subject: [PATCH 3/6] ecc: updates vascular proliferation characteristic description --- ecc/morph/ECC-MORPH-000001.yml | 9 ++------- 1 file changed, 2 insertions(+), 7 deletions(-) diff --git a/ecc/morph/ECC-MORPH-000001.yml b/ecc/morph/ECC-MORPH-000001.yml index 97cf6e6..35025f5 100644 --- a/ecc/morph/ECC-MORPH-000001.yml +++ b/ecc/morph/ECC-MORPH-000001.yml @@ -4,14 +4,9 @@ identifier: ECC-MORPH-000001 rfc: https://github.com/stjudecloud/ecc/issues/7 assignment: morphological description: | - Judah Folkman first discovered the concept of rapid blood vessel growth in 1971, as detailed in his publication in the *New England Journal of Medicine* (NEJM), referenced [here](https://pubmed.ncbi.nlm.nih.gov/4938153/). - His work laid the foundation for further research into angiogenesis, the process of forming new blood vessels. - -evaluation: | - - "Immunohistochemistry (IHC) of angiogenesis-related markers like CD34, VEGF, FVIII-RA, CD31, Ki-67." - - "H&E staining" - - qPCR to measure expression levels of angiopoietins and/or VEGF, https://pubmed.ncbi.nlm.nih.gov/10669954/, https://www.nature.com/articles/3780177 + In 1971, Judah Folkman introduced the groundbreaking concept of rapid blood vessel growth, or angiogenesis, in his seminal publication in the *New England Journal of Medicine* (NEJM) [here](https://pubmed.ncbi.nlm.nih.gov/4938153/). His discovery revolutionized the understanding of vascular biology and provided the foundation for subsequent research into the process of forming new blood vessels, a crucial mechanism in both health and disease. + Several techniques are employed to evaluate angiogenesis and its related processes. These include immunohistochemistry (IHC) to analyze angiogenesis-related markers such as CD34, VEGF, FVIII-RA, CD31, and Ki-67, which are important for understanding the mechanisms of blood vessel formation and proliferation. Hematoxylin and Eosin (H&E) staining is also commonly used to assess tissue structure and angiogenesis by staining cell and tissue components. Additionally, qPCR (Quantitative Polymerase Chain Reaction) is utilized to quantify angiogenesis-related gene expression, particularly focusing on angiopoietins and VEGF. Relevant studies on these methods can be found in sources like [PubMed](https://pubmed.ncbi.nlm.nih.gov/10669954/) and [Nature](https://www.nature.com/articles/3780177). values: kind: binary description: From cac277de0d54fbb5b208cb1dca8d952649bcbff1 Mon Sep 17 00:00:00 2001 From: madetunj Date: Fri, 4 Apr 2025 10:54:10 -0500 Subject: [PATCH 4/6] ecc: update vascular proliferation values fields --- ecc/morph/ECC-MORPH-000001.yml | 17 ++++++----------- 1 file changed, 6 insertions(+), 11 deletions(-) mode change 100644 => 100755 ecc/morph/ECC-MORPH-000001.yml diff --git a/ecc/morph/ECC-MORPH-000001.yml b/ecc/morph/ECC-MORPH-000001.yml old mode 100644 new mode 100755 index 35025f5..1764c3b --- a/ecc/morph/ECC-MORPH-000001.yml +++ b/ecc/morph/ECC-MORPH-000001.yml @@ -11,19 +11,14 @@ values: kind: binary description: "true": - summary: Here is a summary for the 'true' value. + summary: Vascular Proliferation is observed. details: | - Here is a much longer description. + The histologic section reveals prominent vascular proliferation characterized by an increased density of small, thin-walled capillaries dispersed throughout the tissue. The newly formed vessels are lined by plump endothelial cells without significant atypia and are organized in a loosely woven pattern suggestive of active angiogenesis. There may be no evidence of necrosis or hemorrhage, and the proliferation appears to be reactive rather than neoplastic in nature. Immunohistochemical staining for CD34 highlights the expanded vascular network, and Ki-67 demonstrates low proliferative activity within the endothelial cells, supporting a benign process. These findings are consistent with a positive observation of vascular proliferation, likely representing a physiologic or reparative response. - This description is spread across multiple lines. It can be in paragraph - form and should be hardwrapped at 88 characters. "false": - summary: Here is a summary for the 'false' value. + summary: Vascular Proliferation is not observed. details: | - Here is a much longer description. - - This description is spread across multiple lines. It can be in paragraph - form and should be hardwrapped at 88 characters. + The density and distribution of blood vessels appear within normal limits, with no increase in capillary formation or abnormal vascular architecture observed. Endothelial cells lining the vessels are unremarkable, lacking hyperplasia, multilayering, or cytologic atypia. There is no evidence of neovascularization, and immunohistochemical staining for CD34 reveals a normal vascular pattern without expansion or irregularity. These findings indicate the absence of active angiogenesis or abnormal vascular activity within the sampled tissue. references: - kind: manuscript title: Vascular smooth muscle hyperplasia underlies the formation of glomeruloid vascular structures of glioblastoma multiforme @@ -40,7 +35,7 @@ references: url: https://pubmed.ncbi.nlm.nih.gov/3039783/ highlighted: true - kind: manuscript - title: Early and extensive contribution of pericytes/vascular smooth muscle cells to microvascular proliferation in glioblastoma multiforme: an immuno-light and immuno-electron microscopic study + title: Early and extensive contribution of pericytes/vascular smooth muscle cells to microvascular proliferation in glioblastoma multiforme, an immuno-light and immuno-electron microscopic study authors: Wesseling P, Schlingemann RO, Rietveld FJ, Link M, Burger PC, Ruiter DJ context: | Recent studies of glioblastoma multiforme (GBM) microvascular proliferation (MVP) suggest that pericytes and vascular smooth muscle cells (VSMC), not just endothelial cells (EC), play a major role. Immunohistochemical analysis revealed two distinct cell types—EC and pericytes/VSMC—with no transitional forms. Pericytes/VSMC were found to contribute extensively to MVP, particularly in early stages of tumor capillary formation, highlighting their essential role in GBM angiogenesis. @@ -56,4 +51,4 @@ references: authors: Clara CA, Marie SK, de Almeida JR, Wakamatsu A, Oba-Shinjo SM, Uno M, Neville M, Rosemberg S context: | This study analyzed the expression of PDGF-C, VEGF, and HIF-1α in 208 glioblastoma (GBM) cases to understand their role in angiogenesis and prognosis. The results showed that HIF-1α, VEGF, and PDGF-C were highly expressed in most tumors, with HIF-1α expression correlating with increased vascular density and higher VEGF and PDGF-C levels. A significant correlation was found between VEGF and PDGF-C expression in both tumor cells and blood vessels. Endothelial cells with positive VEGF and PDGF-C expression also showed markers of neoangiogenesis and proliferation. Nuclear staining for VEGF and HIF-1α was linked to poorer survival. The findings support the potential benefit of combined anti-angiogenic therapies for improving GBM treatment outcomes. - url: "https://pubmed.ncbi.nlm.nih.gov/24612214/" \ No newline at end of file + url: https://pubmed.ncbi.nlm.nih.gov/24612214/ \ No newline at end of file From 8fb7a5cd5b1b25746df8a9de20f5031803aa97e9 Mon Sep 17 00:00:00 2001 From: madetunj Date: Fri, 18 Apr 2025 15:31:20 -0500 Subject: [PATCH 5/6] update: location provided --- ecc/morph/ECC-MORPH-000001.yml | 6 +++--- 1 file changed, 3 insertions(+), 3 deletions(-) diff --git a/ecc/morph/ECC-MORPH-000001.yml b/ecc/morph/ECC-MORPH-000001.yml index 1764c3b..95ddcbf 100755 --- a/ecc/morph/ECC-MORPH-000001.yml +++ b/ecc/morph/ECC-MORPH-000001.yml @@ -11,12 +11,12 @@ values: kind: binary description: "true": - summary: Vascular Proliferation is observed. + summary: Vascular Proliferation is observed in the sample. details: | The histologic section reveals prominent vascular proliferation characterized by an increased density of small, thin-walled capillaries dispersed throughout the tissue. The newly formed vessels are lined by plump endothelial cells without significant atypia and are organized in a loosely woven pattern suggestive of active angiogenesis. There may be no evidence of necrosis or hemorrhage, and the proliferation appears to be reactive rather than neoplastic in nature. Immunohistochemical staining for CD34 highlights the expanded vascular network, and Ki-67 demonstrates low proliferative activity within the endothelial cells, supporting a benign process. These findings are consistent with a positive observation of vascular proliferation, likely representing a physiologic or reparative response. "false": - summary: Vascular Proliferation is not observed. + summary: Vascular Proliferation is not observed in the sample. details: | The density and distribution of blood vessels appear within normal limits, with no increase in capillary formation or abnormal vascular architecture observed. Endothelial cells lining the vessels are unremarkable, lacking hyperplasia, multilayering, or cytologic atypia. There is no evidence of neovascularization, and immunohistochemical staining for CD34 reveals a normal vascular pattern without expansion or irregularity. These findings indicate the absence of active angiogenesis or abnormal vascular activity within the sampled tissue. references: @@ -51,4 +51,4 @@ references: authors: Clara CA, Marie SK, de Almeida JR, Wakamatsu A, Oba-Shinjo SM, Uno M, Neville M, Rosemberg S context: | This study analyzed the expression of PDGF-C, VEGF, and HIF-1α in 208 glioblastoma (GBM) cases to understand their role in angiogenesis and prognosis. The results showed that HIF-1α, VEGF, and PDGF-C were highly expressed in most tumors, with HIF-1α expression correlating with increased vascular density and higher VEGF and PDGF-C levels. A significant correlation was found between VEGF and PDGF-C expression in both tumor cells and blood vessels. Endothelial cells with positive VEGF and PDGF-C expression also showed markers of neoangiogenesis and proliferation. Nuclear staining for VEGF and HIF-1α was linked to poorer survival. The findings support the potential benefit of combined anti-angiogenic therapies for improving GBM treatment outcomes. - url: https://pubmed.ncbi.nlm.nih.gov/24612214/ \ No newline at end of file + url: https://pubmed.ncbi.nlm.nih.gov/24612214/ From 2b929c6a88cc9c85f448f7a9c169ead8a4c9eef8 Mon Sep 17 00:00:00 2001 From: madetunj Date: Mon, 21 Apr 2025 12:04:56 -0500 Subject: [PATCH 6/6] update: suggested metrics to binary values --- ecc/morph/ECC-MORPH-000001.yml | 16 ++++++++-------- 1 file changed, 8 insertions(+), 8 deletions(-) diff --git a/ecc/morph/ECC-MORPH-000001.yml b/ecc/morph/ECC-MORPH-000001.yml index 95ddcbf..d8a535c 100755 --- a/ecc/morph/ECC-MORPH-000001.yml +++ b/ecc/morph/ECC-MORPH-000001.yml @@ -13,12 +13,12 @@ values: "true": summary: Vascular Proliferation is observed in the sample. details: | - The histologic section reveals prominent vascular proliferation characterized by an increased density of small, thin-walled capillaries dispersed throughout the tissue. The newly formed vessels are lined by plump endothelial cells without significant atypia and are organized in a loosely woven pattern suggestive of active angiogenesis. There may be no evidence of necrosis or hemorrhage, and the proliferation appears to be reactive rather than neoplastic in nature. Immunohistochemical staining for CD34 highlights the expanded vascular network, and Ki-67 demonstrates low proliferative activity within the endothelial cells, supporting a benign process. These findings are consistent with a positive observation of vascular proliferation, likely representing a physiologic or reparative response. + The tissue section demonstrates increased vascular proliferation, characterized by a marked rise in the density of small, thin-walled capillaries concentrated in focal areas. The estimated microvessel density (MVD) is approximately 25 vessels per high-power field (HPF), notably exceeding the expected range for this tissue type. The vessels are lined by plump, occasionally multilayered endothelial cells, and some show irregular architecture suggestive of active neovascularization. CD34 immunostaining highlights an expanded and disorganized vascular network. Ki-67 immunohistochemistry reveals increased proliferative activity among endothelial cells, with a proliferation index of approximately 10%, consistent with active angiogenesis. These features indicate a pathologic vascular response, possibly associated with an underlying neoplastic or reparative process. "false": summary: Vascular Proliferation is not observed in the sample. details: | - The density and distribution of blood vessels appear within normal limits, with no increase in capillary formation or abnormal vascular architecture observed. Endothelial cells lining the vessels are unremarkable, lacking hyperplasia, multilayering, or cytologic atypia. There is no evidence of neovascularization, and immunohistochemical staining for CD34 reveals a normal vascular pattern without expansion or irregularity. These findings indicate the absence of active angiogenesis or abnormal vascular activity within the sampled tissue. + The examined tissue section shows no evidence of abnormal vascular proliferation. The vascular density is within normal histologic limits for the tissue type, with an estimated microvessel density (MVD) of approximately 5 vessels per high-power field (HPF), consistent with baseline physiologic vascularization. The vessels display normal morphology, with a uniform distribution and no evidence of capillary sprouting, endothelial cell hyperplasia, or multilayering. Immunohistochemical staining for CD34 outlines a regular vascular pattern without expansion, and Ki-67 staining reveals minimal proliferative activity in endothelial cells (<1%), indicating a low endothelial proliferation index. These findings support the absence of active angiogenesis or pathologic vascular changes. references: - kind: manuscript title: Vascular smooth muscle hyperplasia underlies the formation of glomeruloid vascular structures of glioblastoma multiforme @@ -40,15 +40,15 @@ references: context: | Recent studies of glioblastoma multiforme (GBM) microvascular proliferation (MVP) suggest that pericytes and vascular smooth muscle cells (VSMC), not just endothelial cells (EC), play a major role. Immunohistochemical analysis revealed two distinct cell types—EC and pericytes/VSMC—with no transitional forms. Pericytes/VSMC were found to contribute extensively to MVP, particularly in early stages of tumor capillary formation, highlighting their essential role in GBM angiogenesis. url: https://pubmed.ncbi.nlm.nih.gov/7745429/ - - kind: manuscript - title: Genetic modulation of hypoxia induced gene expression and angiogenesis, relevance to brain tumors - authors: Brat DJ, Kaur B, Van Meir EG - context: | - Angiogenesis, crucial for the growth of infiltrative astrocytomas, manifests as "microvascular hyperplasia" in glioblastoma multiforme, the most aggressive form. This abnormal vascular proliferation, often linked to necrosis, is driven by hypoxic conditions within the tumor and genetic alterations. Hypoxia upregulates pro-angiogenic factors like VEGF through the HIF-1 pathway, which is influenced by genetic changes in oncogenes and tumor suppressor genes such as PTEN, TP53, and EGFR. These genetic alterations also impact the expression of other angiogenic factors, further promoting tumor angiogenesis. - url: https://pubmed.ncbi.nlm.nih.gov/12456339/ - kind: manuscript title: Angiogenesis and expression of PDGF-C, VEGF, CD105 and HIF-1α in human glioblastoma authors: Clara CA, Marie SK, de Almeida JR, Wakamatsu A, Oba-Shinjo SM, Uno M, Neville M, Rosemberg S context: | This study analyzed the expression of PDGF-C, VEGF, and HIF-1α in 208 glioblastoma (GBM) cases to understand their role in angiogenesis and prognosis. The results showed that HIF-1α, VEGF, and PDGF-C were highly expressed in most tumors, with HIF-1α expression correlating with increased vascular density and higher VEGF and PDGF-C levels. A significant correlation was found between VEGF and PDGF-C expression in both tumor cells and blood vessels. Endothelial cells with positive VEGF and PDGF-C expression also showed markers of neoangiogenesis and proliferation. Nuclear staining for VEGF and HIF-1α was linked to poorer survival. The findings support the potential benefit of combined anti-angiogenic therapies for improving GBM treatment outcomes. url: https://pubmed.ncbi.nlm.nih.gov/24612214/ + - kind: manuscript + title: Genetic modulation of hypoxia induced gene expression and angiogenesis, relevance to brain tumors + authors: Brat DJ, Kaur B, Van Meir EG + context: | + Angiogenesis, crucial for the growth of infiltrative astrocytomas, manifests as "microvascular hyperplasia" in glioblastoma multiforme, the most aggressive form. This abnormal vascular proliferation, often linked to necrosis, is driven by hypoxic conditions within the tumor and genetic alterations. Hypoxia upregulates pro-angiogenic factors like VEGF through the HIF-1 pathway, which is influenced by genetic changes in oncogenes and tumor suppressor genes such as PTEN, TP53, and EGFR. These genetic alterations also impact the expression of other angiogenic factors, further promoting tumor angiogenesis. + url: https://pubmed.ncbi.nlm.nih.gov/12456339/