Desmoplasia

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-plasia and -trophy
  • Abiotrophy (loss in vitality of organ or tissue)
  • Atrophy (reduced functionality of an organ, with decrease in the number or volume of cells)
  • Hypertrophy (increase in the volume of cells or tissues)
  • Hypotrophy (decrease in the volume of cells or tissues)
  • Dystrophy (any degenerative disorder resulting from improper or faulty nutrition)
Desmoplastic small round cell tumour, with desmoplasia surrounding nests of cancer cells. Desmoplastic small round cell tumour - intermed mag.jpg
Desmoplastic small round cell tumour, with desmoplasia surrounding nests of cancer cells.

In medicine, desmoplasia is the growth of fibrous connective tissue. [1] It is also called a desmoplastic reaction to emphasize that it is secondary to an insult. Desmoplasia may occur around a neoplasm, causing dense fibrosis around the tumor, [1] or scar tissue (adhesions) within the abdomen after abdominal surgery. [1]

Contents

Desmoplasia is usually only associated with malignant neoplasms, which can evoke a fibrotic response invading healthy tissue. Invasive ductal carcinomas of the breast often have a stellate appearance caused by desmoplastic formations.

Terminology

Desmoplasia originates from the Ancient Greek δεσμόςdesmos, 'knot, bond' and πλάσιςplasis, 'formation'. It is usually used in the description of desmoplastic small round cell tumors.

Neoplasia is the medical term used for both benign and malignant tumors, or any abnormal, excessive, uncoordinated, and autonomous cellular or tissue growth.

Desmoplastic reaction to breast cancer Breast cancer 00454.jpg
Desmoplastic reaction to breast cancer

Desmoplasia refers to growth of dense connective tissue or stroma. [2] This growth is characterized by low cellularity with hyalinized or sclerotic stroma and disorganized blood vessel infiltration. [3] This growth is called a desmoplastic response and occurs as result of injury or neoplasia. [2] This response is coupled with malignancy in non-cutaneous neoplasias, and with benign or malignant tumors if associated with cutaneous pathologies. [3]

The heterogeneity of tumor cancer cells and stroma cells combined with the complexities of surrounding connective tissue suggest that understanding cancer by tumor cell genomic analysis is not sufficient; [4] analyzing the cells together with the surrounding stromal tissue may provide more comprehensive and meaningful data.

Normal tissue structure and wound response

Normal tissues consist of parenchymal cells and stromal cells. The parenchymal cells are the functional units of an organ. In contrast, the stromal cells provide the structure of the organ and secrete extracellular matrix as supportive, connective tissue. [3] In normal epithelial tissues, epithelial cells, or parenchymal cells of epithelia, are highly organized, polar cells. [5] These cells are separated from stromal cells by a basement membrane that prevents these cell populations from mixing. [5] A mixture of these cell types is recognized, normally, as a wound, as in the example of a cut to the skin. [6] Metastasis is an example of a disease state in which a breach of the basement membrane barrier occurs. [7]

Cancer

Micrographs of loose, moderate and dense desmoplastic stroma in pancreatic ductal adenocarcinoma, as seen with H&E stain (top row), Masson's trichrome stain (middle row) and a-smooth muscle actin. Micrograph of loose, moderate and dense desmoplastic stroma in pancreatic ductal adenocarcinoma.jpg
Micrographs of loose, moderate and dense desmoplastic stroma in pancreatic ductal adenocarcinoma, as seen with H&E stain (top row), Masson's trichrome stain (middle row) and α-smooth muscle actin.

Cancer begins as cells that grow uncontrollably, usually as a result of an internal change or oncogenic mutations within the cell. [8] Cancer develops and progresses as the microenvironment undergoes dynamic changes. [9] The stromal reaction in cancer is similar to the stromal reaction induced by injury or wound repair: increased extracellular matrix (ECM) and growth factor production and secretion, which consequently cause growth of the tissue. [10] In other words, the body reacts similarly to a cancer as it does to a wound, causing scar-like tissue to be built around the cancer. As such, the surrounding stroma plays a very important role in the progression of cancer. The interaction between cancer cells and surrounding tumor stroma is thus bidirectional, and the mutual cellular support allows for the progression of the malignancy.

Growth factors for vascularization, migration, degradation, proliferation

Stroma contains extracellular matrix components such as proteoglycans and glycosaminoglycans which are highly negatively charged, largely due to sulfated regions, and bind growth factors and cytokines, acting as a reservoir of these cytokines. [5] In tumors, cancer cells secrete matrix degrading enzymes, such as matrix metalloproteinases (MMPs) that, once cleaved and activated, degrade the matrix, thereby releasing growth factors that signal for the growth of cancer cells. [11] MMPs also degrade ECM to provide space for vasculature to grow to the tumor, for the tumor cells to migrate, and for the tumor to continue to proliferate. [3]

Underlying mechanisms

Desmoplasia is thought to have a number of underlying causes. In the reactive stroma hypothesis, tumor cells cause the proliferation of fibroblasts and subsequent secretion of collagen. [3] The newly secreted collagen is similar to that of collagen in scar formation – acting as a scaffold for infiltration of cells to the site of injury. [12] Furthermore, the cancer cells secrete matrix degrading enzymes to destroy normal tissue ECM thereby promoting growth and invasiveness of the tumor. [3] Cancer associated with a reactive stroma is typically diagnostic of poor prognosis. [3]

The tumor-induced stromal change hypothesis claims that tumor cells can dedifferentiate into fibroblasts and, themselves, secrete more collagen. [3] This was observed in desmoplastic melanoma, in which the tumor cells are phenotypically fibroblastic and positively express genes associated with ECM production. [13] However, benign desmoplasias do not exhibit dedifferentiation of tumor cells. [3]

Characteristics of desmoplastic stromal response

A desmoplastic response is characterized by larger stromal cells with increased extracellular fibers and immunohistochemically by transformation of fibroblastic-type cells to a myofibroblastic phenotype. [2] Myofibroblastic cells in tumors are differentiated from fibroblasts for their positive staining of smooth-muscle actin (SMA). [2] Furthermore, an increase in total fibrillar collagens, fibronectins, proteoglycans, and tenascin C are distinctive of the desmoplastic stromal response in several forms of cancer. [14] Expression of tenascin C by breast cancer cells has been demonstrated to allow for metastasis to the lungs and cause the expression of tenascin C by the surrounding tumor stromal cells. [15] In addition, tenascin C is found extensively in pancreatic tumor desmoplasia as well. [16]

Differentiation of scars

While scars are associated with the desmoplastic response of various cancers, not all scars are associated with malignant neoplasms. [3] Mature scars are usually thick, collagenous bundles arranged horizontally with paucicellularity, vertical blood vessels, and no appendages. [3] This is distinguished from desmoplasia in the organization of the tissue, the appendages, and orientation of blood vessels. Immature scars are more difficult to distinguish due to their neoplastic origins. [3] These scars are hypercellular with fibroblasts, myofibroblasts, and some immune cells present. [3] The immature scars can be distinguished from desmoplasia by immunohistochemical staining of biopsied tumors that will reveal the type and organization of cells present as well as whether recent trauma has occurred to the tissue. [17]

Examples

Source: [3]

Benign condition examples

Desmoplasia around surgical suture material. Histopathology of suture material.jpg
Desmoplasia around surgical suture material.
  1. Desmoplastic melanocytic naevus
  2. Desmoplastic spitz naevus
  3. Desmoplastic cellular blue naevus
  4. Desmoplastic hairless hypopigmented naevus
  5. Desmoplastic trichoepithelioma
  6. Desmoplastic trichilemmoma
  7. Desmoplastic tumor of the follicular infundibulum
  8. Sclerotic dermatofibroma
  9. Desmoplastic fibroblastoma
  10. Desmoplastic cellular neurothekeoma
  11. Sclerosing perineurioma
  12. Microvenular haemangioma
  13. Immature scars

Malignant condition examples

  1. Desmoplastic malignant melanoma
  2. Desmoplastic squamous cell carcinoma
  3. Morpheaform basal cell carcinoma
  4. Microcystic adnexal carcinoma
  5. Cutaneous leiomyosarcoma
  6. Cutaneous metastasis

Prostate cancer

The stroma of the prostate is characteristically muscular. [2] Due to this muscularity, detecting the myofibroblastic phenotypic change indicative of reactive stroma is difficult in an examination of patient pathologic slides. [2] A diagnosis of reactive stroma associated with prostate cancer is one of poor prognosis. [2]

Breast cancer

Clinical presentation of a lump in the breast is histologically viewed as a collagenous tumor or desmoplastic response created by myofibroblasts of the tumor stroma. [18] Proposed mechanisms of activation of myofibroblasts are by immune cytokine signaling, microvascular injury, or paracrine signaling by tumor cells. [18]

See also

Related Research Articles

<span class="mw-page-title-main">Fibroblast</span> Animal connective tissue cell

A fibroblast is a type of biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework (stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells of connective tissue in animals.

<span class="mw-page-title-main">Fibronectin</span> Protein involved in cell adhesion, cell growth, cell migration and differentiation

Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collagen, fibrin, and heparan sulfate proteoglycans.

<span class="mw-page-title-main">Metastasis</span> Spread of a disease inside a body

Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, are metastases (mets). It is generally distinguished from cancer invasion, which is the direct extension and penetration by cancer cells into neighboring tissues.

<span class="mw-page-title-main">Extracellular matrix</span> Network of proteins and molecules outside cells that provides structural support for cells

In biology, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and biochemical support to surrounding cells. Because multicellularity evolved independently in different multicellular lineages, the composition of ECM varies between multicellular structures; however, cell adhesion, cell-to-cell communication and differentiation are common functions of the ECM.

Stromal cells, or mesenchymal stromal cells, are differentiating cells found in abundance within bone marrow but can also be seen all around the body. Stromal cells can become connective tissue cells of any organ, for example in the uterine mucosa (endometrium), prostate, bone marrow, lymph node and the ovary. They are cells that support the function of the parenchymal cells of that organ. The most common stromal cells include fibroblasts and pericytes. The term stromal comes from Latin stromat-, "bed covering", and Ancient Greek στρῶμα, strôma, "bed".

Intravasation is the invasion of cancer cells through the basement membrane into a blood or lymphatic vessel. Intravasation is one of several carcinogenic events that initiate the escape of cancerous cells from their primary sites. Other mechanisms include invasion through basement membranes, extravasation, and colonization of distant metastatic sites. Cancer cell chemotaxis also relies on this migratory behavior to arrive at a secondary destination designated for cancer cell colonization.

<span class="mw-page-title-main">MMP2</span> Protein-coding gene in humans

72 kDa type IV collagenase also known as matrix metalloproteinase-2 (MMP-2) and gelatinase A is an enzyme that in humans is encoded by the MMP2 gene. The MMP2 gene is located on chromosome 16 at position 12.2.

<span class="mw-page-title-main">Fibroblast activation protein, alpha</span>

Fibroblast activation protein alpha (FAP-alpha) also known as prolyl endopeptidase FAP is an enzyme that in humans is encoded by the FAP gene.

<span class="mw-page-title-main">Periostin</span> Protein-coding gene in the species Homo sapiens

Periostin is a protein that in humans is encoded by the POSTN gene. Periostin functions as a ligand for alpha-V/beta-3 and alpha-V/beta-5 integrins to support adhesion and migration of epithelial cells.

<span class="mw-page-title-main">Dermatopontin</span> Protein-coding gene in the species Homo sapiens

Dermatopontin also known as tyrosine-rich acidic matrix protein (TRAMP) is a protein that in humans is encoded by the DPT gene. Dermatopontin is a 22-kDa protein of the noncollagenous extracellular matrix (ECM) estimated to comprise 12 mg/kg of wet dermis weight. To date, homologues have been identified in five different mammals and 12 different invertebrates with multiple functions. In vertebrates, the primary function of dermatopontin is a structural component of the ECM, cell adhesion, modulation of TGF-β activity and cellular quiescence). It also has pathological involvement in heart attacks and decreased expression in leiomyoma and fibrosis. In invertebrate, dermatopontin homologue plays a role in hemagglutination, cell-cell aggregation, and expression during parasite infection.

Pancreatic stellate cells (PaSCs) are classified as myofibroblast-like cells that are located in exocrine regions of the pancreas. PaSCs are mediated by paracrine and autocrine stimuli and share similarities with the hepatic stellate cell. Pancreatic stellate cell activation and expression of matrix molecules constitute the complex process that induces pancreatic fibrosis. Synthesis, deposition, maturation and remodelling of the fibrous connective tissue can be protective, however when persistent it impedes regular pancreatic function.

<span class="mw-page-title-main">Metastatic breast cancer</span> Type of cancer

Metastatic breast cancer, also referred to as metastases, advanced breast cancer, secondary tumors, secondaries or stage IV breast cancer, is a stage of breast cancer where the breast cancer cells have spread to distant sites beyond the axillary lymph nodes. There is no cure for metastatic breast cancer; there is no stage after IV.

<span class="mw-page-title-main">Mammary-type myofibroblastoma</span> Medical condition

Mammary-type myofibroblastoma (MFB), also named mammary and extramammary myofibroblastoma, was first termed myofibrolastoma of the breast, or, more simply, either mammary myofibroblastoma (MMFB) or just myofibroblastoma. The change in this terminology occurred because the initial 1987 study and many subsequent studies found this tumor only in breast tissue. However, a 2001 study followed by numerous reports found tumors with the microscopic histopathology and other key features of mammary MFB in a wide range of organs and tissues. Further complicating the issue, early studies on MFB classified it as one of various types of spindle cell tumors that, except for MFB, were ill-defined. These other tumors, which have often been named interchangeably in different reports, are: myelofibroblastoma, benign spindle cell tumor, fibroma, spindle cell lipoma, myogenic stromal tumor, and solitary stromal tumor. Finally, studies suggest that spindle cell lipoma and cellular angiofibroma are variants of MFB. Here, the latter two tumors are tentatively classified as MFB variants but otherwise MFB is described as it is more strictly defined in most recent publications. The World Health Organization in 2020 classified mammary type myofibroblastoma tumors and myofibroblastoma tumors as separate tumor forms within the category of fibroblastic and myofibroblastic tumors.

<span class="mw-page-title-main">Tumor microenvironment</span> Surroundings of tumors including nearby cells and blood vessels

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A cancer-associated fibroblast (CAF) is a cell type within the tumor microenvironment that promotes tumorigenic features by initiating the remodelling of the extracellular matrix or by secreting cytokines. CAFs are a complex and abundant cell type within the tumour microenvironment; the number cannot decrease, as they are unable to undergo apoptosis.

<span class="mw-page-title-main">Invasion (cancer)</span> Direct extension and penetration by cancer cells into neighboring tissues

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References

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  2. 1 2 3 4 5 6 7 Ayala, G; Tuxhorn, JA; Wheeler, TM; Frolov, A; Scardino, PT; Ohori, M; Wheeler, M; Spitler, J; Rowley, DR (2003). "Reactive stroma as a predictor of biochemical-free recurrence in prostate cancer". Clinical Cancer Research. 9 (13): 4792–801. PMID   14581350.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Liu, H; Ma, Q; Xu, Q; Lei, J; Li, X; Wang, Z; Wu, E (2012). "Therapeutic potential of perineural invasion, hypoxia and desmoplasia in pancreatic cancer". Current Pharmaceutical Design. 18 (17): 2395–403. doi:10.2174/13816128112092395. PMC   3414721 . PMID   22372500.
  4. ↑ Hanahan, Douglas; Weinberg, Robert A. (2011). "Hallmarks of Cancer: The Next Generation". Cell. 144 (5): 646–74. doi: 10.1016/j.cell.2011.02.013 . PMID   21376230.
  5. 1 2 3 Alberts, B; Johnson, A; Lewis, J (2008). Molecular Biology of the Cell (5th ed.). Garland Science, Taylor & Francis Group. pp. 1164–1165, 1178–1195.
  6. ↑ Mort, Richard L; Ramaesh, Thaya; Kleinjan, Dirk A; Morley, Steven D; West, John D (2009). "Mosaic analysis of stem cell function and wound healing in the mouse corneal epithelium". BMC Developmental Biology. 9: 4. doi: 10.1186/1471-213X-9-4 . PMC   2639382 . PMID   19128502.
  7. ↑ Liotta, LA (1984). "Tumor invasion and metastases: Role of the basement membrane. Warner-Lambert Parke-Davis Award lecture". The American Journal of Pathology. 117 (3): 339–48. PMC   1900581 . PMID   6095669.
  8. ↑ Steen, H. B. (2000). "The origin of oncogenic mutations: Where is the primary damage?". Carcinogenesis. 21 (10): 1773–6. doi: 10.1093/carcin/21.10.1773 . PMID   11023532.
  9. ↑ Kraning-Rush, Casey M.; Califano, Joseph P.; Reinhart-King, Cynthia A. (2012). Laird, Elizabeth G. (ed.). "Cellular Traction Stresses Increase with Increasing Metastatic Potential". PLOS ONE. 7 (2): e32572. Bibcode:2012PLoSO...732572K. doi: 10.1371/journal.pone.0032572 . PMC   3289668 . PMID   22389710.
  10. ↑ Troester, M. A.; Lee, M. H.; Carter, M.; Fan, C.; Cowan, D. W.; Perez, E. R.; Pirone, J. R.; Perou, C. M.; et al. (2009). "Activation of Host Wound Responses in Breast Cancer Microenvironment". Clinical Cancer Research. 15 (22): 7020–8. doi:10.1158/1078-0432.CCR-09-1126. PMC   2783932 . PMID   19887484.
  11. ↑ Foda, Hussein D; Zucker, Stanley (2001). "Matrix metalloproteinases in cancer invasion, metastasis and angiogenesis". Drug Discovery Today. 6 (9): 478–482. doi:10.1016/S1359-6446(01)01752-4. PMID   11344033.
  12. ↑ El-Torkey, M; Giltman, LI; Dabbous, M (1985). "Collagens in scar carcinoma of the lung". The American Journal of Pathology. 121 (2): 322–6. PMC   1888060 . PMID   3904470.
  13. ↑ Walsh, NM; Roberts, JT; Orr, W; Simon, GT (1988). "Desmoplastic malignant melanoma. A clinicopathologic study of 14 cases". Archives of Pathology & Laboratory Medicine. 112 (9): 922–7. PMID   3415443.
  14. ↑ Kalluri, Raghu; Zeisberg, Michael (2006). "Fibroblasts in cancer". Nature Reviews Cancer. 6 (5): 392–401. doi:10.1038/nrc1877. PMID   16572188. S2CID   20357911.
  15. ↑ Oskarsson, Thordur; Acharyya, Swarnali; Zhang, Xiang H-F; Vanharanta, Sakari; Tavazoie, Sohail F; Morris, Patrick G; Downey, Robert J; Manova-Todorova, Katia; et al. (2011). "Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs". Nature Medicine. 17 (7): 867–74. doi:10.1038/nm.2379. PMC   4020577 . PMID   21706029.
  16. ↑ Esposito, I; Penzel, R; Chaib-Harrireche, M; Barcena, U; Bergmann, F; Riedl, S; Kayed, H; Giese, N; et al. (2006). "Tenascin C and annexin II expression in the process of pancreatic carcinogenesis". The Journal of Pathology. 208 (5): 673–85. doi:10.1002/path.1935. PMID   16450333. S2CID   26993700.
  17. ↑ Kaneishi, Nelson K.; Cockerell, Clay J. (1998). "Histologic Differentiation of Desmoplastic Melanoma from Cicatrices". The American Journal of Dermatopathology. 20 (2): 128–34. doi:10.1097/00000372-199804000-00004. PMID   9557779.
  18. 1 2 Walker, Rosemary A (2001). "The complexities of breast cancer desmoplasia". Breast Cancer Research. 3 (3): 143–5. doi: 10.1186/bcr287 . PMC   138677 . PMID   11305947.
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